Azepino[4,5-b]indoles and methods of use

ABSTRACT

This disclosure relates to new azepino[4,5-b]indole compounds that may be used to modulate a histamine receptor in an individual. Novel compounds are described, including new 1,2,3,4,5,6-tetrahydroazepino[4,5-b]indoles. Pharmaceutical compositions are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 61/110,527 filed Oct. 31, 2008, U.S. Provisional Patent ApplicationNo. 61/173,965 filed Apr. 29, 2009 and U.S. Provisional PatentApplication No. 61/245,257 filed Sep. 23, 2009, the disclosures of eachof which are hereby incorporated herein by reference in theirentireties.

STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH

Not applicable.

BACKGROUND OF THE INVENTION

Neurotransmitters such as histamine, serotonin, dopamine andnorepinephrine mediate a large number of processes in the centralnervous system (CNS) as well as outside the CNS. Abnormalneurotransmitter levels are associated with a wide variety of diseasesand conditions including, but not limited to, Alzheimer's disease,Parkinson's Disease, autism, ADD, ADHD, Guillain-Barré syndrome, mildcognitive impairment, schizophrenia (such as cognitive impairmentassociated with schizophrenia (CIAS), positive symptoms, disorganizedsymptoms, and negative symptoms of schizophrenia), anxiety, multiplesclerosis, stroke, traumatic brain injury, spinal cord injury, diabeticneuropathy, fibromyalgia, bipolar disorders, psychosis, depression,attention-deficit disorder (ADD), attention-deficit hyperactivitydisorder (ADHD) and a variety of allergic diseases. Compounds thatmodulate these neurotransmitters may be useful therapeutics.

Histamine receptors belong to the superfamily of G protein-coupled seventransmembrane proteins. G protein-coupled receptors constitute one ofthe major signal transduction systems in eukaryotic cells. Codingsequences for these receptors, in those regions believed to contributeto the agonist-antagonist binding site, are strongly conserved acrossmammalian species. Histamine receptors are found in most peripheraltissue and within the central nervous system. Compounds capable ofmodulating a histamine receptor may find use in therapy, e.g., histamineantagonists may find use as antihistamines.

Dimebon is a known anti-histamine drug that has also been characterizedas a neuroprotective agent useful to treat, inter alia,neurodegenerative diseases. Dimebon has been shown to inhibit the deathof brain cells (neurons) in preclinical models of Alzheimer's diseaseand Huntington's disease, making it a novel potential treatment forthese and other neurodegenerative diseases. In addition, dimebon hasbeen shown to improve the mitochondrial function of cells in the settingof cellular stress with very high potency. For example, dimebontreatment improved mitochondrial function and increased the number ofsurviving cells after treatment with the cell toxin ionomycin in a dosedependent fashion. Dimebon has also been shown to promote neuriteoutgrowth and neurogenesis, processes important in the formation of newand/or enhanced neuronal cell connections, and evidence of dimebon'spotential for use in additional diseases or conditions. See, e.g., U.S.Pat. Nos. 6,187,785 and 7,071,206 and PCT Patent Application Nos.PCT/US2004/041081, PCT/US2007/020483, PCT/US2006/039077,PCT/U52008/077090, PCT/U52007/020516, PCT/US2007/022645,PCT/US2007/002117, PCT/US2008/006667, PCT/US2007/024626,PCT/U52008/009357, PCT/US2007/024623, PCT/US2008/008121, andPCT/US2009/032065. Hydrogenated pyrido[4,3-b]indoles and uses thereofhave been disclosed in PCT Patent Application Nos. PCT/US2008/081390,PCT/US2009/032065 and PCT/US2009/038142. Hydrogenatedpyrido[3,4-b]indoles and uses thereof have been described inPCT/US2009/038138. All references disclosed herein and throughout, suchas publications, patents, patent applications and published patentapplications, are incorporated herein by reference in their entireties.

Although dimebon holds great promise as a drug for the treatment ofneurodegenerative diseases and/or diseases in which neurite outgrowthand/or neurogenesis may be implicated in therapy, there remains a needfor new and alternative therapies for the treatment of such diseases orconditions. In addition, there remains a need for new and alternativeantihistamine drugs, preferably ones in which side-effects such asdrowsiness are reduced or eliminated. Compounds that exhibit enhancedand/or more desirable properties than dimebon (e.g., superior safety andefficacy) may find particular use in the treatment of at least thoseindications for which dimebon is believed to be advantageous. Further,compounds that exhibit a different therapeutic profile than dimebon asdetermined, e.g. by in vitro and/or in vivo assays, may find use inadditional diseases and conditions.

BRIEF SUMMARY OF THE INVENTION

Azepino[4,5-b]indole compounds of the general Formula (I) are describedas new histamine receptor modulators. Other compounds are also detailedherein. Compositions comprising the compounds are provided, as are kitscomprising the compound as well as methods of using and making thecompounds. Compounds of the invention may also find use in treatingneurodegenerative diseases. Compounds of the invention may also find usein treating diseases and/or conditions in which modulation of aminergicG protein-coupled receptors and/or neurite outgrowth may be implicatedin therapy. Compounds disclosed herein may find use in the methodsdisclosed herein, including use in treating, preventing, delaying theonset and/or delaying the development of a cognitive disorder, psychoticdisorder, neurotransmitter-mediated disorder and/or a neuronal disorderin an individual in need thereof, such as humans.

The invention embraces compounds of the formula (I):

where:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy;

each R^(2a), R^(2b), R^(3a) and R^(3b) is independently H, hydroxyl,nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is takentogether with the carbon to which it is attached and a geminal R² or R³to form a cycloalkyl moiety or a carbonyl moiety;

each R^(10a), R^(10b), R^(11a) and R^(11b) is independently H, hydroxyl,nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together withthe carbon to which it is attached and a geminal R¹⁰ or R¹¹ to form acycloalkyl moiety or a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each of m and q is independently 0 or 1;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, alkoxy, halo, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈alkenyl, or is taken together with a geminal R⁸ to form a moiety of theformula —OCH₂CH₂O—, is taken together with the carbon to which it isattached and a geminal R⁸ to form a cycloalkyl moiety or a carbonylmoiety, is taken together with a geminal R⁸ to form a methylene or asubstituted methylene, is taken together with a vicinal R⁸ and thecarbon atoms to which they are attached to form a substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or istaken together with a vicinal R⁸ to form a bond, provided when an R⁸ istaken together with a vicinal R⁸ to form a bond, the geminal R⁸ is otherthan hydroxyl;

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano oralkynyl;

provided that the compound is other than a compound in Table 1;

or a salt or solvate thereof.

In one variation, the compounds of the invention, pharmaceuticalcompositions thereof, isolated forms thereof and methods of using andadministering the compounds detailed herein, encompass any of thecompounds of Formula (I), including those listed in Table 1 or a saltthereof.

TABLE 1 Compound No. Compound Structure  1x 1-Propanone,3-(diethylamino)-1-[1,4,5,6-tetrahydro-6-(phenylmethyl)azepino[4,5-b]indol-3(2H)-yl]-  2x Azepino[4,5-b]indol-4(1H)-one,2,3,5,6-tetrahydro-3,5,6-tris(phenylmethyl)-  3xAzepino[4,5-b]indol-4(1H)-one, 2,3,5,6-tetrahydro-3,6-bis(phenylmethyl)- 4x Azepino[4,5-b]indol-4(1H)-one,2,3,5,6-tetrahydro-5-(2-oxo-2-phenylethyl)-3,6- bis(phenylmethyl)-  5xAzepino[4,5-b]indol-4(1H)-one,2,3,5,6-tetrahydro-5-(2-oxo-2-phenylethyl)-6- (phenylmethyl)-  6xAzepino[4,5-b]indol-4(1H)-one, 2,3,5,6-tetrahydro-5,5-diphenyl-3,6-bis(phenylmethyl)-  7x Azepino[4,5-b]indol-4(1H)-one,2,3,5,6-tetrahydro-5,5-diphenyl-6-(phenylmethyl)-  8xAzepino[4,5-b]indol-4(1H)-one, 2,3,5,6-tetrahydro-5,6-bis(phenylmethyl)- 9x Azepino[4,5-b]indol-4(1H)-one,2,3,5,6-tetrahydro-5-phenyl-3,6-bis(phenylmethyl)-  10xAzepino[4,5-b]indol-4(1H)-one,2,3,5,6-tetrahydro-5-phenyl-6-(phenylmethyl)-  11xAzepino[4,5-b]indol-4(1H)-one, 2,3,5,6-tetrahydro-6-(phenylmethyl)-  12xAzepino[4,5-b]indol-5(2H)-one,1,3,4,6-tetrahydro-3-methyl-6-(phenylmethyl)-  13xAzepino[4,5-b]indol-5-ol,1,2,3,4,5,6-hexahydro-6-(m-methoxybenzyl)-3-methyl-  14xAzepino[4,5-b]indol-5-ol,1,2,3,4,5,6-hexahydro-8-methoxy-6-(m-methoxybenzyl)- 3-methyl-  15xAzepino[4,5-b]indol-5-ol, 6-benzyl-1,2,3,4,5,6-hexahydro-3-methyl-  16xAzepino[4,5-b]indol-5-ol, 6-benzyl-1,2,3,4,5,6-hexahydro-3-methyl-,acetate (ester)  17x Azepino[4,5-b]indol-5-ol,6-benzyl-3-ethyl-1,2,3,4,5,6-hexahydro-  18x Azepino[4,5-b]indol-5-ol,6-benzyl-3-ethyl-1,2,3,4,5,6-hexahydro-8-methoxy-  19xAzepino[4,5-b]indol-5-ol,6-benzyl-9-chloro-1,2,3,4,5,6-hexahydro-3-methyl-  20xAzepino[4,5-b]indole, 1,2,3,4,5,6-hexahydro-3,5,6-tris(phenylmethyl)- 21x Azepino[4,5-b]indole, 1,2,3,4,5,6-hexahydro-3,6-bis(phenylmethyl)- 22x Azepino[4,5-b]indole,1,2,3,4,5,6-hexahydro-3-methyl-6-(2-pyridylmethyl)-  23xAzepino[4,5-b]indole,1,2,3,4,5,6-hexahydro-3-methyl-6-(alpha-methylbenzyl)-  24xAzepino[4,5-b]indole, 1,2,3,4,5,6-hexahydro-3-methyl-6-[3-(4-methyl-1-piperazinyl)propyl]-  25x Azepino[4,5-b]indole,1,2,3,4,5,6-hexahydro-5,5-diphenyl-3,6-bis(phenylmethyl)-  26xAzepino[4,5-b]indole,1,2,3,4,5,6-hexahydro-5,5-diphenyl-6-(phenylmethyl)-  27xAzepino[4,5-b]indole, 1,2,3,4,5,6-hexahydro-5,6-bis(phenylmethyl)-  28xAzepino[4,5-b]indole,1,2,3,4,5,6-hexahydro-5-phenyl-3,6-bis(phenylmethyl)-  29xAzepino[4,5-b]indole, 1,2,3,4,5,6-hexahydro-5-phenyl-6-(phenylmethyl)- 30x Azepino[4,5-b]indole, 1,2,3,4,5,6-hexahydro-6-(phenylmethyl)-  31xAzepino[4,5-b]indole,1,2,3,4,5,6-hexahydro-6-[(3-methoxyphenyl)methyl]-3- methyl-  32xAzepino[4,5-b]indole,10-chloro-1,2,3,4,5,6-hexahydro-3-methyl-6-(phenylmethyl)-  33xAzepino[4,5-b]indole,10-chloro-3-ethyl-1,2,3,4,5,6-hexahydro-6-(phenylmethyl)-  34xAzepino[4,5-b]indole,3-(1H-benzimidazol-2-ylmethyl)-1,2,3,4,5,6-hexahydro-5-phenyl-6-(phenylmethyl)-  35x Azepino[4,5-b]indole,3-(3-chloro-1-oxopropyl)-1,2,3,4,5,6-hexahydro-6- (phenylmethyl)- (9CI) 36x Azepino[4,5-b]indole,3-(chloroacetyl)-1,2,3,4,5,6-hexahydro-5-phenyl-6- (phenylmethyl)-  37xAzepino[4,5-b]indole,3-ethyl-1,2,3,4,5,6-hexahydro-10-methyl-6-(phenylmethyl)-  38xAzepino[4,5-b]indole,3-ethyl-1,2,3,4,5,6-hexahydro-8-methoxy-6-(phenylmethyl)-  39xAzepino[4,5-b]indole,3-ethyl-1,2,3,4,5,6-hexahydro-8-methyl-6-(phenylmethyl)-  40xAzepino[4,5-b]indole,3-ethyl-1,2,3,4,5,6-hexahydro-9-methyl-6-(phenylmethyl)  41xAzepino[4,5-b]indole,6-(1H-benzimidazol-2-ylmethyl)-10-bromo-1,2,3,4,5,6- hexahydro-  42xAzepino[4,5-b]indole,6-[(2-chlorophenyl)methyl]-1,2,3,4,5,6-hexahydro-3-methyl-  43xAzepino[4,5-b]indole,6-[(4-chlorophenyl)methyl]-3-ethyl-1,2,3,4,5,6-hexahydro-  44xAzepino[4,5-b]indole, 6-benzyl-1,2,3,4,5,6-hexahydro-3-methyl-  45xAzepino[4,5-b]indole, 6-benzyl-3-ethyl-1,2,3,4,5,6-hexahydro-  46xAzepino[4,5-b]indole,8,9-dichloro-1,2,3,4,5,6-hexahydro-6-(3-phenylpropyl)-  47xAzepino[4,5-b]indole,8-chloro-1,2,3,4,5,6-hexahydro-3-methyl-6-(phenylmethyl)-  48xAzepino[4,5-b]indole,8-chloro-3-ethyl-1,2,3,4,5,6-hexahydro-6-(phenylmethyl)-  49xAzepino[4,5-b]indole,9,10-dichloro-1,2,3,4,5,6-hexahydro-6-(3-phenylpropyl)-  50xAzepino[4,5-b]indole,9-chloro-1,2,3,4,5,6-hexahydro-3-methyl-6-(phenylmethyl)-  51xAzepino[4,5-b]indole,9-chloro-3-ethyl-1,2,3,4,5,6-hexahydro-6-(phenylmethyl)-  52xAzepino[4,5-b]indole-3(2H)-carboxylic acid, 1,4,5,6-tetrahydro-6-[2-(phenylamino)ethyl]-, 1,1-dimethylethyl ester  53xAzepino[4,5-b]indole-3(2H)-carboxylic acid, 1,4,5,6-tetrahydro-6-[2-[(3-methylphenyl)amino]-2-oxoethyl-, 1,1-dimethylethyl ester  54xAzepino[4,5-b]indole-3(2H)-carboxylic acid, 1,4,5,6-tetrahydro-6-[2-[(4-methoxyphenyl)amino]-2-oxoethyl]-, 1,1-dimethylethyl ester  55xAzepino[4,5-b]indole-3(2H)-carboxylic acid, 1,4,5,6-tetrahydro-6-[2-[[(phenylamino)carbonyl]amino]ethyl]-, 1,1-dimethylethyl ester  56xAzepino[4,5-b]indole-3(2H)-carboxylicacid,1,4,5,6-tetrahydro-6-[2-oxo-2- (phenylamino)ethyl]-,1,1-dimethylethyl ester  57x Azepino[4,5-b]indole-3(2H)-carboxylic acid,1,4,5,6-tetrahydro-6-[2-oxo-2-[(2,4,6- trimethylphenyl)amino]ethyl]-,1,1-dimethylethyl ester  58x Azepino[4,5-b]indole-3(2H)-carboxylic acid,1,4,5,6-tetrahydro-6-[3-[(4- methoxyphenyl)amino]-3-oxopropyl]-,1,1-dimethylethyl ester  59x Azepino[4,5-b]indole-3(2H)-carboxylic acid,10-bromo-1,4,5,6-tetrahydro-6-[2-[(4-methyl-2-thiazolyl)amino]-2-oxoethyl]-, 1,1-dimethylethyl ester  60xAzepino[4,5-b]indole-3(2H)-carboxylic acid,6-(1H-benzimidazol-2-ylmethyl)-10- bromo-1,4,5,6-tetrahydro-,1,1-dimethylethyl ester  61x Azepino[4,5-b]indole-3(2H)-carboxylic acid,6-(2-amino-2-oxoethyl)-1,4,5,6- tetrahydro-, 1,1-dimethylethyl ester 62x Azepino[4,5-b]indole-3(2H)-carboxylic acid,6-(2-aminoethyl)-1,4,5,6-tetrahydro-, 1,1-dimethylethyl ester  65xAzepino[4,5-b]indole-3(2H)-carboxylic acid,6-[2-(benzoylamino)ethyl]-1,4,5,6- tetrahydro-, 1,1-dimethylethyl ester 66x Azepino[4,5-b]indole-3(2H)-carboxylic acid,6-[2-(dimethylamino)-2-oxoethyl]- 1,4,5,6-tetrahydro-, 1,1-dimethylethylester  67x Azepino[4,5-b]indole-3(2H)-carboxylic acid,6-[2-[(2,3-dimethylphenyl)amino]-2- oxoethyl]-1,4,5,6-tetrahydro-,1,1-dimethylethyl ester  68x Azepino[4,5-b]indole-3(2H)-carboxylic acid,6-[2-[(2-fluoro-4- methylphenyl)amino]-2-oxoethyl]-1,4,5,6-tetrahydro-,1,1-dimethylethyl ester  69x Azepino[4,5-b]indole-3(2H)-carboxylic acid,7-bromo-1,4,5,6-tetrahydro-6-[2-[(4-methyl-2-thiazolyl)amino]-2-oxoethyl]-, 1,1-dimethylethyl ester  70xAzepino[4,5-b]indole-3(2H)-carboxylic acid,8,9-dichloro-1,4,5,6-tetrahydro-6-(3- phenylpropyl)-, 1,1-dimethylethylester  71x Azepino[4,5-b]indole-3(2H)-carboxylic acid,8,9-dichloro-1,4,5,6-tetrahydro-6-[2-[(4-methoxyphenyl)amino]-2-oxoethyl]-, 1,1-dimethylethyl ester  72xAzepino[4,5-b]indole-3(2H)-carboxylic acid,8,9-dichloro-1,4,5,6-tetrahydro-6-[2- oxo-2-(phenylamino)ethyl]-,1,1-dimethylethyl ester  73x Azepino[4,5-b]indole-3(2H)-carboxylic acid,8,9-dichloro-6-[2-[(2,3-dimethylphenyl)amino]-2-oxoethyl]-1,4,5,6-tetrahydro-, 1,1-dimethylethylester  74x Azepino[4,5-b]indole-3(2H)-carboxylic acid,9,10-dichloro-1,4,5,6-tetrahydro-6-(3- phenylpropyl)-, 1,1-dimethylethylester  75x Azepino[4,5-b]indole-3(2H)-carboxylic acid,9,10-dichloro-1,4,5,6-tetrahydro-6-[2-[(4-methoxyphenyl)amino]-2-oxoethyl]-, 1,1-dimethylethyl ester  76xAzepino[4,5-b]indole-3(2H)-carboxylic acid,9,10-dichloro-1,4,5,6-tetrahydro-6-[2-oxo-2-(phenylamino)ethyl]-,1,1-dimethylethyl ester  77xAzepino[4,5-b]indole-3(2H)-carboxylic acid, 9,10-dichloro-6-[2-[(2,3-dimethylphenyl)amino]-2-oxoethyl]-1,4,5,6-tetrahydro-, 1,1-dimethylethylester  78x Azepino[4,5-b]indole-3,6-dicarboxylic acid,5-[3,3-dimethoxy-2- (methoxycarbonyl)propyl]-1,2,4,5-tetrahydro-,3,6-bis(1,1-dimethylethyl) ester  80xAzepino[4,5-b]indole-6(1H)-acetamide, 2,3,4,5-tetrahydro-  81xAzepino[4,5-b]indole-6(1H)-acetamide, 2,3,4,5-tetrahydro-N,N-dimethyl- 82x Azepino[4,5-b]indole-6(1H)-acetamide,2,3,4,5-tetrahydro-N-2-pyridinyl-  83xAzepino[4,5-b]indole-6(1H)-acetamide, 2,3,4,5-tetrahydro-N-3-pyridinyl- 84x Azepino[4,5-b]indole-6(1H)-acetamide, 2,3,4,5-tetrahydro-N-phenyl- 85x Azepino[4,5-b]indole-6(1H)-acetamide,10-bromo-2,3,4,5-tetrahydro-N-(4-methyl-2- thiazolyl)-  86xAzepino[4,5-b]indole-6(1H)-acetamide, 2,3,4,5-tetrahydro-N-(2,4,6-trimethylphenyl)-  87x Azepino[4,5-b]indole-6(1H)-acetamide,2,3,4,5-tetrahydro-N-(3-methoxyphenyl)-  88xAzepino[4,5-b]indole-6(1H)-acetamide,2,3,4,5-tetrahydro-N-(3-methylphenyl)-  89xAzepino[4,5-b]indole-6(1H)-acetamide,2,3,4,5-tetrahydro-N-(3-nitrophenyl)-  90xAzepino[4,5-b]indole-6(1H)-acetamide,2,3,4,5-tetrahydro-N-(4-methoxyphenyl)-  91xAzepino[4,5-b]indole-6(1H)-acetamide,2,3,4,5-tetrahydro-N-(4-methyl-2-thiazolyl)- 92x Azepino[4,5-b]indole-6(1H)-acetamide,2,3,4,5-tetrahydro-N-(5,6,7,8-tetrahydro-1- naphthalenyl)-  93xAzepino[4,5-b]indole-6(1H)-acetamide, 2,3,4,5-tetrahydro-N-[2-methyl-3-(trifluoromethyl)phenyl]-  94x Azepino[4,5-b]indole-6(1H)-acetamide,7,10-dichloro-2,3,4,5-tetrahydro-N-(4- methyl-2-thiazolyl)-  95xAzepino[4,5-b]indole-6(1H)-acetamide,7,10-dichloro-2,3,4,5-tetrahydro-N-(4- phenyl-2-thiazolyl)-  96xAzepino[4,5-b]indole-6(1H)-acetamide,7,10-dichloro-2,3,4,5-tetrahydro-N-(5,6,7,8- tetrahydro-1-naphthalenyl)- 97x Azepino[4,5-b]indole-6(1H)-acetamide,7,10-dichloro-2,3,4,5-tetrahydro-N-(5- methyl-2-thiazolyl)-  98xAzepino[4,5-b]indole-6(1H)-acetamide,7,10-dichloro-2,3,4,5-tetrahydro-N-[3-(1- methylethyl)phenyl]-  99xAzepino[4,5-b]indole-6(1H)-acetamide,7,10-dichloro-N-(2,3-dimethylphenyl)- 2,3,4,5-tetrahydro- 100xAzepino[4,5-b]indole-6(1H)-acetamide,7,10-dichloro-N-(3-ethylphenyl)-2,3,4,5- tetrahydro- 101xAzepino[4,5-b]indole-6(1H)-acetamide, 7,10-dichloro-N-[3-(1,1-dimethylethyl)phenyl]-2,3,4,5-tetrahydro- 102xAzepino[4,5-b]indole-6(1H)-acetamide,7,10-dichloro-N-[4-(1,1-dimethylethyl)-2- thiazolyl]-2,3,4,5-tetrahydro-103x Azepino[4,5-b]indole-6(1H)-acetamide,7,8-dichloro-2,3,4,5-tetrahydro-N-(4- methyl-2-thiazolyl)- 104xAzepino[4,5-b]indole-6(1H)-acetamide,7,8-dichloro-2,3,4,5-tetrahydro-N-(4- phenyl-2-thiazolyl)- 105xAzepino[4,5-b]indole-6(1H)-acetamide,7,8-dichloro-2,3,4,5-tetrahydro-N-(5,6,7,8- tetrahydro-1-naphthalenyl)-106x Azepino[4,5-b]indole-6(1H)-acetamide,7,8-dichloro-2,3,4,5-tetrahydro-N-(5- methyl-2-thiazolyl)- 107xAzepino[4,5-b]indole-6(1H)-acetamide,7,8-dichloro-2,3,4,5-tetrahydro-N-[3-(1- methylethyl)phenyl]- 108xAzepino[4,5-b]indole-6(1H)-acetamide,7,8-dichloro-N-(2,3-dimethylphenyl)- 2,3,4,5-tetrahydro- 109xAzepino[4,5-b]indole-6(1H)-acetamide,7,8-dichloro-N-(3-ethylphenyl)-2,3,4,5- tetrahydro- 110xAzepino[4,5-b]indole-6(1H)-acetamide, 7,8-dichloro-N-[3-(1,1-dimethylethyl)phenyl]-2,3,4,5-tetrahydro- 111xAzepino[4,5-b]indole-6(1H)-acetamide,7,8-dichloro-N-[4-(1,1-dimethylethyl)-2- thiazolyl]-2,3,4,5-tetrahydro-112x Azepino[4,5-b]indole-6(1H)-acetamide,7,9-dichloro-2,3,4,5-tetrahydro-N-(4- methyl-2-thiazolyl)- 113xAzepino[4,5-b]indole-6(1H)-acetamide,7,9-dichloro-2,3,4,5-tetrahydro-N-(4- phenyl-2-thiazolyl)- 114xAzepino[4,5-b]indole-6(1H)-acetamide,7,9-dichloro-2,3,4,5-tetrahydro-N-(5,6,7,8- tetrahydro-1-naphthalenyl)-115x Azepino[4,5-b]indole-6(1H)-acetamide,7,9-dichloro-2,3,4,5-tetrahydro-N-(5- methyl-2-thiazolyl)- 116xAzepino[4,5-b]indole-6(1H)-acetamide,7,9-dichloro-2,3,4,5-tetrahydro-N-[3-(1- methylethyl)phenyl]- 117xAzepino[4,5-b]indole-6(1H)-acetamide,7,9-dichloro-N-(2,3-dimethylphenyl)- 2,3,4,5-tetrahydro- 118xAzepino[4,5-b]indole-6(1H)-acetamide,7,9-dichloro-N-(3-ethylphenyl)-2,3,4,5- tetrahydro- 119xAzepino[4,5-b]indole-6(1H)-acetamide, 7,9-dichloro-N-[3-(1,1-dimethylethyl)phenyl]-2,3,4,5-tetrahydro- 120xAzepino[4,5-b]indole-6(1H)-acetamide,7,9-dichloro-N-[4-(1,1-dimethylethyl)-2- thiazolyl]-2,3,4,5-tetrahydro-121x Azepino[4,5-b]indole-6(1H)-acetamide,7-bromo-2,3,4,5-tetrahydro-N-(4- methoxyphenyl)- 122xAzepino[4,5-b]indole-6(1H)-acetamide,7-bromo-2,3,4,5-tetrahydro-N-(4-methyl-2- thiazolyl)- 123xAzepino[4,5-b]indole-6(1H)-acetamide,8,10-dichloro-2,3,4,5-tetrahydro-N-(4- methyl-2-thiazolyl)- 124xAzepino[4,5-b]indole-6(1H)-acetamide,8,10-dichloro-2,3,4,5-tetrahydro-N-(4-phenyl-2-thiazolyl)- 125x Azepino[4,5-b]indole-6(1H)-acetamide,8,10-dichloro-2,3,4,5-tetrahydro-N-(5,6,7,8- tetrahydro-1-naphthalenyl)-126x Azepino[4,5-b]indole-6(1H)-acetamide,8,10-dichloro-2,3,4,5-tetrahydro-N-(5- methyl-2-thiazolyl)- 127xAzepino[4,5-b]indole-6(1H)-acetamide,8,10-dichloro-2,3,4,5-tetrahydro-N-[3-(1- methylethyl)phenyl]- 128xAzepino[4,5-b]indole-6(1H)-acetamide,8,10-dichloro-N-(2,3-dimethylphenyl)- 2,3,4,5-tetrahydro- 129xAzepino[4,5-b]indole-6(1H)-acetamide,8,10-dichloro-N-(3-ethylphenyl)-2,3,4,5-tetrahydro- 130x Azepino[4,5-b]indole-6(1H)-acetamide,8,10-dichloro-N-[3-(1,1- dimethylethyl)phenyl]-2,3,4,5-tetrahydro- 131xAzepino[4,5-b]indole-6(1H)-acetamide,8,10-dichloro-N-[4-(1,1-dimethylethyl)-2- thiazolyl]-2,3,4,5-tetrahydro-132x Azepino[4,5-b]indole-6(1H)-acetamide,8,9-dichloro-2,3,4,5-tetrahydro-N-(4- methoxyphenyl)- 133xAzepino[4,5-b]indole-6(1H)-acetamide,8,9-dichloro-2,3,4,5-tetrahydro-N-(4- methyl-2-thiazolyl)- 134xAzepino[4,5-b]indole-6(1H)-acetamide,8,9-dichloro-2,3,4,5-tetrahydro-N-(4- phenyl-2-thiazolyl)- 135xAzepino[4,5-b]indole-6(1H)-acetamide,8,9-dichloro-2,3,4,5-tetrahydro-N-(5,6,7,8- tetrahydro-1-naphthalenyl)-136x Azepino[4,5-b]indole-6(1H)-acetamide,8,9-dichloro-2,3,4,5-tetrahydro-N-(5- methyl-2-thiazolyl)- 137xAzepino[4,5-b]indole-6(1H)-acetamide,8,9-dichloro-2,3,4,5-tetrahydro-N-[3-(1- methylethyl)phenyl]- 138xAzepino[4,5-b]indole-6(1H)-acetamide,8,9-dichloro-2,3,4,5-tetrahydro-N-phenyl- 139xAzepino[4,5-b]indole-6(1H)-acetamide,8,9-dichloro-N-(2,3-dimethylphenyl)- 2,3,4,5-tetrahydro- 140xAzepino[4,5-b]indole-6(1H)-acetamide,8,9-dichloro-N-(3-ethylphenyl)-2,3,4,5- tetrahydro- 141xAzepino[4,5-b]indole-6(1H)-acetamide, 8,9-dichloro-N-[3-(1,1-dimethylethyl)phenyl]-2,3,4,5-tetrahydro- 142xAzepino[4,5-b]indole-6(1H)-acetamide,8,9-dichloro-N-[4-(1,1-dimethylethyl)-2- thiazolyl]-2,3,4,5-tetrahydro-143x Azepino[4,5-b]indole-6(1H)-acetamide,8-bromo-2,3,4,5-tetrahydro-N-(4-methyl-2- thiazolyl)- 144xAzepino[4,5-b]indole-6(1H)-acetamide,9,10-dichloro-2,3,4,5-tetrahydro-N-(4- methoxyphenyl)- 145xAzepino[4,5-b]indole-6(1H)-acetamide,9,10-dichloro-2,3,4,5-tetrahydro-N-(4- methyl-2-thiazolyl)- 146xAzepino[4,5-b]indole-6(1H)-acetamide,9,10-dichloro-2,3,4,5-tetrahydro-N-(4- phenyl-2-thiazolyl)- 147xAzepino[4,5-b]indole-6(1H)-acetamide,9,10-dichloro-2,3,4,5-tetrahydro-N-(5,6,7,8- tetrahydro-1-naphthalenyl)-148x Azepino[4,5-b]indole-6(1H)-acetamide,9,10-dichloro-2,3,4,5-tetrahydro-N-(5- methyl-2-thiazolyl)- 149xAzepino[4,5-b]indole-6(1H)-acetamide,9,10-dichloro-2,3,4,5-tetrahydro-N-[3-(1- methylethyl)phenyl]- 150xAzepino[4,5-b]indole-6(1H)-acetamide,9,10-dichloro-2,3,4,5-tetrahydro-N-phenyl- 151xAzepino[4,5-b]indole-6(1H)-acetamide,9,10-dichloro-N-(2,3-dimethylphenyl)- 2,3,4,5-tetrahydro- 152xAzepino[4,5-b]indole-6(1H)-acetamide,9,10-dichloro-N-(3-ethylphenyl)-2,3,4,5-tetrahydro- 153x Azepino[4,5-b]indole-6(1H)-acetamide,9,10-dichloro-N-[3-(1,1- dimethylethyl)phenyl]-2,3,4,5-tetrahydro- 154xAzepino[4,5-b]indole-6(1H)-acetamide,9,10-dichloro-N-[4-(1,1-dimethylethyl)-2- thiazolyl]-2,3,4,5-tetrahydro-155x Azepino[4,5-b]indole-6(1H)-acetamide,9-bromo-2,3,4,5-tetrahydro-N-(4-methyl-2- thiazolyl)- 156xAzepino[4,5-b]indole-6(1H)-acetamide,N-(1,3-dihydro-4-isobenzofuranyl)-2,3,4,5- tetrahydro- 157xAzepino[4,5-b]indole-6(1H)-acetamide,N-(2,3-dimethylphenyl)-2,3,4,5-tetrahydro- 158xAzepino[4,5-b]indole-6(1H)-acetamide, N-(2,4-dimethoxyphenyl)-2,3,4,5-tetrahydro- 159x Azepino[4,5-b]indole-6(1H)-acetamide,N-(2-fluoro-4-methylphenyl)-2,3,4,5- tetrahydro- 160xAzepino[4,5-b]indole-6(1H)-acetamide, N-(3,5-dimethoxyphenyl)-2,3,4,5-tetrahydro- 161x Azepino[4,5-b]indole-6(1H)-acetamide,N-(3-chloro-2-methylphenyl)-2,3,4,5- tetrahydro- 162xAzepino[4,5-b]indole-6(1H)-acetamide,N-(3-chloro-4-fluorophenyl)-2,3,4,5- tetrahydro- 163xAzepino[4,5-b]indole-6(1H)-acetamide,N-(4-cyanophenyl)-2,3,4,5-tetrahydro- 164xAzepino[4,5-b]indole-6(1H)-acetamide,N-(4-fluorophenyl)-2,3,4,5-tetrahydro- 165xAzepino[4,5-b]indole-6(1H)-acetamide,N-2-benzothiazolyl-7,10-dichloro-2,3,4,5- tetrahydro- 166xAzepino[4,5-b]indole-6(1H)-acetamide,N-2-benzothiazolyl-7,8-dichloro-2,3,4,5- tetrahydro- 167xAzepino[4,5-b]indole-6(1H)-acetamide,N-2-benzothiazolyl-7,9-dichloro-2,3,4,5- tetrahydro- 168x Azepino[4,5-b]indole-6(1H)-acetamide, N-2-benzothiazolyl-8,10-dichloro-2,3,4,5-tetrahydro- 169x Azepino[4,5-b]indole-6(1H)-acetamide,N-2-benzothiazolyl-8,9-dichloro-2,3,4,5- tetrahydro- 170xAzepino[4,5-b]indole-6(1H)-acetamide,N-2-benzothiazolyl-9,10-dichloro-2,3,4,5- tetrahydro- 171xAzepino[4,5-b]indole-6(1H)-acetic acid, 10-bromo-2,3,4,5-tetrahydro-, 2-methylpropyl ester 172x Azepino[4,5-b]indole-6(1H)-acetic acid,9,10-dichloro-2,3,4,5-tetrahydro-, ethyl ester 173xAzepino[4,5-b]indole-6(1H)-ethanamine, 2,3,4,5-tetrahydro- 174xAzepino[4,5-b]indole-6(1H)-ethanamine, 2,3,4,5-tetrahydro-N-phenyl- 176xAzepino[4,5-b]indole-6(1H)-propanamide,2,3,4,5-tetrahydro-N-(4-methoxyphenyl)- 177xAzepino[4,5-b]indole-6(1H)-propanamine,2,3,4,5-tetrahydro-N,N,3,9-tetramethyl- 178xAzepino[4,5-b]indole-6(1H)-propanamine,2,3,4,5-tetrahydro-N,N,3-trimethyl- 179xAzepino[4,5-b]indole-6(1H)-propanoic acid,3-benzoyl-2,3,4,5-tetrahydro-, ethyl ester 180xAzepino[4,5-b]indole-6-acetic acid,10-bromo-3-[(1,1-dimethylethoxy)carbonyl]- 1,2,4,5-tetrahydro-, ethylester 181x Azepino[4,5-b]indole-6-acetic acid,10-bromo-3-[(1,1-dimethylethoxy)carbonyl]- 1,2,4,5-tetrahydro-,2-methylpropyl ester 182x Azepino[4,5-b]indole-6-acetic acid,3-[(1,1-dimethylethoxy)carbonyl]-1,2,4,5- tetrahydro-, ethyl ester 183xAzepino[4,5-b]indole-6-acetic acid,3-[(1,1-dimethylethoxy)carbonyl]-1,2,4,5- tetrahydro-7-nitro-, ethylester 184x Azepino[4,5-b]indole-6-acetic acid,7,10-dichloro-3-[(1,1-dimethylethoxy)carbonyl]- 1,2,4,5-tetrahydro-,ethyl ester 185x Azepino[4,5-b]indole-6-acetic acid,7,8-dichloro-3-[(1,1-dimethylethoxy)carbonyl]- 1,2,4,5-tetrahydro-,ethyl ester 186x Azepino[4,5-b]indole-6-acetic acid,7,9-dichloro-3-[(1,1-dimethylethoxy)carbonyl]- 1,2,4,5-tetrahydro-,ethyl ester 187x Azepino[4,5-b]indole-6-acetic acid,8,10-dichloro-3-[(1,1-dimethylethoxy)carbonyl]- 1,2,4,5-tetrahydro-,ethyl ester 188x Azepino[4,5-b]indole-6-acetic acid,8,9-dichloro-3-[(1,1-dimethylethoxy)carbonyl]- 1,2,4,5-tetrahydro-,ethyl ester 189x Azepino[4,5-b]indole-6-acetic acid,9,10-dichloro-3-[(1,1-dimethylethoxy)carbonyl]- 1,2,4,5-tetrahydro-,ethyl ester 190x Azepino[4,5-b]indole-9-carboxylic acid,1,2,3,4,5,6-hexahydro-3-methyl-6- (phenylmethyl)-, ethyl ester 191xBenzamide, N-[2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl]-192x Ethanone, 2-(diethylamino)-1-[1,4,5,6-tetrahydro-5-phenyl-6-(phenylmethyl)azepino[4,5-b]indol-3(2H)-yl]- 193x Ethanone,2-[1,2,3,4,5,6-hexahydro-3,6-bis(phenylmethyl)azepino[4,5-b]indol-5-yl]-1-phenyl- 194x Ethanone,2-[1,2,3,4,5,6-hexahydro-6-(phenylmethyl)azepino[4,5-b]indol-5-yl]-1-phenyl-

The invention also embraces compounds of the formula (I) wherein each ofm and q is 0 (Formula (Ia)). In another variation, the compound is ofthe formula (I) wherein each of m and q is 1 (Formula (Ib)). In anothervariation, the compound is of the formula (I) wherein m=1 and q=0(Formula (Ic)). In one embodiment, the compound is of the formula (I)wherein m=1, q=0 and R^(8C) and R^(8e) are taken together to form a bond(Formula (C)).

In another variation, the compound is of the formula (I), (Ia), (Ib),(Ic) or (C) or any variation thereof detailed herein where Q is asubstituted or unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkenyl, or substituted or a unsubstituted heterocyclyl, or a saltor solvate thereof. In one variation, the compound is of the formula(I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein,where Q is a carbocycle, such as a 5, 6 or 7 membered carbocycle. In onevariation, the compound is of the formula (I), (Ia), (Ib), (Ic) or (C)or any variation thereof detailed herein, where Q is a heterocycle, suchas a 5, 6 or 7 membered carbocycle.

In another variation, the compound is of the formula (I), (Ia), (Ib),(Ic) or (C) or any variation thereof detailed herein where Q issubstituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, or a salt or solvate thereof. In another variation, thecompound is of the formula (I), (Ia), (Ib), (Ic) or (C) or any variationthereof detailed herein where Q is substituted or unsubstitutedheteroaryl, such as a 5, 6 or 7 membered heteroaryl. In one variation,the compound is of the formula (I), (Ia), (Ib), (Ic) or (C) or anyvariation thereof detailed herein where Q is a substituted orunsubstituted aryl, such as a 5, 6 or 7 membered aryl, or a salt orsolvate thereof.

The invention also includes all salts of compounds referred to herein,such as pharmaceutically acceptable salts. The invention also includesany or all of the stereochemical forms, including any enantiomeric ordiastereomeric forms, of the compounds described. Unless stereochemistryis explicitly indicated in a chemical structure or name, the structureor name is intended to embrace all possible stereoisomers, includinggeometric isomers, of a compound depicted. Unless olefin geometry isexplicitly indicated, substituted olefinic bonds may be present as cisor trans or (Z) or (E) isomeric forms, or as mixtures thereof. Inaddition, where a specific stereochemical form is depicted, it isunderstood that other stereochemical forms are also embraced by theinvention. For example, where only a Z form of a compound isspecifically listed, it is understood that the E form of the compound isalso embraced. All forms of the compounds are also embraced by theinvention, such as crystalline or non-crystalline forms of thecompounds. Compositions comprising a compound of the invention are alsointended, such as a composition of substantially pure compound,including a specific stereochemical form thereof. Compositionscomprising a mixture of compounds of the invention in any ratio are alsoembraced by the invention, including mixtures of two or morestereochemical forms of a compound of the invention in any ratio, suchthat racemic, non-racemic, enantioenriched and scalemic mixtures of acompound are embraced.

The invention is also directed to pharmaceutical compositions comprisinga compound of the invention and a pharmaceutically acceptable carrier orexcipient. Kits comprising a compound of the invention and instructionsfor use are also embraced by this invention. Compounds as detailedherein or a pharmaceutically acceptable salt thereof are also providedfor the manufacture of a medicament for the treatment of a cognitivedisorder, psychotic disorder, neurotransmitter-mediated disorder or aneuronal disorder.

The invention also includes all salts of compounds referred to herein,such as pharmaceutically acceptable salts. The invention also includesany or all of the stereochemical forms, including any enantiomeric ordiastereomeric forms, and any tautomers or other forms of the compoundsdescribed. Unless stereochemistry is explicitly indicated in a chemicalstructure or name, the structure or name is intended to embrace allpossible stereoisomers of a compound depicted. In addition, where aspecific stereochemical form is depicted, it is understood that otherstereochemical forms are also embraced by the invention. All forms ofthe compounds are also embraced by the invention, such as crystalline ornon-crystalline forms of the compounds. Compositions comprising acompound of the invention are also intended, such as a composition ofsubstantially pure compound, including a specific stereochemical formthereof. Compositions comprising a mixture of compounds of the inventionin any ratio are also embraced by the invention, including mixtures oftwo or more stereochemical forms of a compound of the invention in anyratio, such that racemic, non-racemic, enantioenriched and scalemicmixtures of a compound are embraced.

In one aspect, compounds of the invention are used to treat, prevent,delay the onset and/or delay the development of any one or more of thefollowing: cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders inindividuals in need thereof, such as humans. In one variation, compoundsof the invention are used to treat, prevent, delay the onset and/ordelay the development of diseases or conditions for which the modulationof an aminergic G protein-coupled receptor is believed to be or isbeneficial. In one variation, compounds of the invention are used totreat, prevent, delay the onset and/or delay the development of any oneor more of diseases or conditions for which neurite outgrowth and/orneurogenesis and/or neurotrophic effects are believed to be or arebeneficial. In another variation, compounds of the invention are used totreat, prevent, delay the onset and/or delay the development of diseasesor conditions for which the modulation of an aminergic G protein-coupledreceptor and neurite outgrowth and/or neurogenesis and/or neurotrophiceffects are believed to be or are beneficial. In one variation, thedisease or condition is a cognitive disorder, psychotic disorder,neurotransmitter-mediated disorder and/or a neuronal disorder.

In another aspect, compounds of the invention are used to improvecognitive function and/or reduce psychotic effects in an individual,comprising administering to an individual in need thereof an amount of acompound described herein or a pharmaceutically acceptable salt thereofeffective to improve cognitive function and/or reduce psychotic effects.

In a further aspect, compounds of the invention are used to stimulateneurite outgrowth and/or promote neurogenesis and/or enhanceneurotrophic effects in an individual comprising administering to anindividual in need thereof an amount of a compound described herein or apharmaceutically acceptable salt thereof effective to stimulate neuriteoutgrowth and/or to promote neurogenesis and/or to enhance neurotrophiceffects. Synapse loss is associated with a variety of neurodegenerativediseases and conditions including Alzheimer's disease, schizophrenia,Huntington's disease, Parkinson's disease, amyotrophic lateralsclerosis, stroke, head trauma and spinal cord injury. Compounds of theinvention that stimulate neurite outgrowth may have a benefit in thesesettings.

In another aspect, compounds described herein are used to modulate anaminergic G protein-coupled receptor comprising administering to anindividual in need thereof an amount of a compound described herein or apharmaceutically acceptable salt thereof effective to modulate anaminergic G protein-coupled receptor. In one variation, a compound ofthe invention modulates at least one of the following receptors:adrenergic receptor (e.g., α_(1D), α_(2A) and/or α_(2B)), serotoninreceptor (e.g., 5-HT_(2A), 5-HT_(2C), 5-HT₆ and/or 5-HT₇), dopaminereceptor (e.g., D_(2L)) and histamine receptor (e.g., H₁, H₂ and/or H₃).In another variation, at least two of the following receptors aremodulated: adrenergic receptor (e.g., α_(1D), α_(2A) and/or α_(2B)),serotonin receptor (e.g., 5-HT_(2A), 5-HT_(2C), 5-HT₆ and/or 5-HT₇),dopamine receptor (e.g., D_(2L)) and histamine receptor (e.g., H₁, H₂and/or H₃). In another variation, at least three of the followingreceptors are modulated: adrenergic receptor (e.g., α_(1D), α_(2A)and/or α_(2B)), serotonin receptor (e.g., 5-HT_(2A), 5-HT_(2C), 5-HT₆and/or 5-HT₇), dopamine receptor (e.g., D_(2L)) and histamine receptor(e.g., H₁, H₂ and/or H₃). In another variation, each of the followingreceptors is modulated: adrenergic receptor (e.g., α_(1D), α_(2A) and/orα_(2B)), serotonin receptor (e.g., 5-HT_(2A), 5-HT_(2C), 5-HT₆ and/or5-HT₇), dopamine receptor (e.g., D_(2L)) and histamine receptor (e.g.,H₁, H₂ and/or H₃). In another variation, at least one of the followingreceptors is modulated: a1D, a2A, a2B, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D₂,H1, H2 and H3. In another variation, at least one of the followingreceptors is modulated: α_(1D), α_(2A), α_(2B), 5-HT_(2A), 5-HT_(2C),5-HT₆, 5-HT₇, D_(2L), H₁, H₂ and H₃. In another variation, at least twoor three or four or five or six or seven or eight or nine or ten oreleven of the following receptors are modulated: a1D, a2A, a2B, 5-HT2A,5-HT2C, 5-HT6, 5-HT7, D₂, H1, H2 and H3. In another variation, at leasttwo or three or four or five or six or seven or eight or nine or ten oreleven of the following receptors are modulated: α_(1D), α_(2A), α_(2B),5-HT_(2A), 5-HT_(2C), 5-HT₆, 5-HT₇, D_(2L), H₁, H₂ and H₃. In stillanother variation, at least dopamine receptor D_(2L) is modulated. Inanother particular variation, at least dopamine receptor D₂ andserotonin receptor 5-HT2A are modulated. In a particular variation, atleast dopamine receptor D_(2L) is modulated. In another particularvariation, at least dopamine receptor D_(2L) and serotonin receptor5-HT_(2A) are modulated. In a further particular variation, at leastadrenergic receptors α_(1D), α_(2A), α_(2B) and serotonin receptor 5-HT₆are modulated. In another particular variation, at least adrenergicreceptors α_(1D), α_(2A), α_(2B), serotonin receptor 5-HT₆ and one ormore of serotonin receptor 5-HT₇, 5-HT_(2A), 5-HT_(2C) and histaminereceptor H₁ and H₂ are modulated. In a further particular variation,histamine receptor H₁ is modulated. In another variation, compounds ofthe invention exhibit any receptor modulation activity detailed hereinand further stimulate neurite outgrowth and/or neurogenesis and/orenhance neurotrophic effects. In one variation, compounds detailedherein inhibit binding of a ligand to histamine receptor H₁ and/or H₂ byless than about 80% as determined by a suitable assay known in the artsuch as the assays described herein. In another variation, binding of aligand to histamine receptor H₁ and/or H₂ is inhibited by less thanabout any of 75%, 70%, 65%, 60%, 55%, or 50% as determined by a suitableassay known in the art such as the assays described herein. In a furthervariation, compounds detailed herein: (a) inhibit binding of a ligand tohistamine receptor H₁ and/or H₂ by less than about 80% (which can indifferent variations be less than about any of 75%, 70%, 65%, 60%, 55%,or 50%) as determined by a suitable assay known in the art such as theassays described herein and (b) inhibit binding of a ligand to dopaminereceptor D_(2L) by greater than about any of 80%, 85%, 90%, 95%, 100% orbetween about 85% and about 95% or between about 90% and about 100%, asdetermined in a suitable assay known in the art such as the assaysdescribed herein. In a further variation, compounds detailed herein: (a)inhibit binding of a ligand to histamine receptor H1 and/or H2 by lessthan about 80% (which can in different variations be less than about anyof 75%, 70%, 65%, 60%, 55%, or 50%) as determined by a suitable assayknown in the art such as the assays described herein and (b) inhibitbinding of a ligand to a dopamine receptor D₂ by greater than about anyof 80%, 85%, 90%, 95%, 100% or between about 85% and about 95% orbetween about 90% and about 100%, as determined in a suitable assayknown in the art such as the assays described herein.

The invention is also directed to pharmaceutical compositions comprisinga compound of the invention and a pharmaceutically acceptable carrier orexcipient. Kits comprising a compound of the invention and instructionsfor use are also embraced by this invention.

Compounds of the formula (I) are provided:

where:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy;

each R^(2a), R^(2b), R^(3a) and R^(3b) is independently H, hydroxyl,nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is takentogether with the carbon to which it is attached and a geminal R² or R³to form a cycloalkyl moiety or a carbonyl moiety;

each R^(10a), R^(10b), R^(11a) and R^(11b) is independently H, hydroxyl,nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together withthe carbon to which it is attached and a geminal R¹⁰ or R¹¹ to form acycloalkyl moiety or a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each m and q is independently 0 or 1;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, alkoxy, halo, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₂-C₈alkenyl, or is taken together with a geminal R⁸ to form a moiety of theformula —OCH₂CH₂O—, is taken together with the carbon to which it isattached and a geminal R⁸ to form a cycloalkyl moiety or a carbonylmoiety, is taken together with a geminal R⁸ to form a methylene or asubstituted methylene, is taken together with a vicinal R⁸ and thecarbon atoms to which they are attached to form a substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or istaken together with a vicinal R⁸ to form a bond, provided when an R⁸ istaken together with a vicinal R⁸ to form a bond, the geminal R⁸ is otherthan hydroxyl;

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano oralkynyl;

or a salt or solvate thereof. In one aspect, compounds are of theformula (I) where, if applicable, any one or more of the followingapply: X⁷, X⁸, X⁹ and X¹⁰ are CR⁴; at least one of X⁷, X⁸, X⁹ and X¹⁰ isN; at least two of X⁷, X⁸, X⁹ and X¹⁰ are N; two of X⁷, X⁸, X⁹ and X¹⁰are N and two of X⁷, X⁸, X⁹ and X¹⁰ are CR⁴; one of X⁷, X⁸, X⁹ and X¹⁰is N and three of X⁷, X⁸, X⁹ and X¹⁰ are CR⁴; if present, each R⁴ isindependently H, halo, substituted or unsubstituted C₁-C₈ alkyl, C₁-C₈perhaloalkyl, substituted or unsubstituted heterocyclyl or a substitutedor unsubstituted aryl; if present, each R⁴ is independently H or asubstituted or unsubstituted C₁-C₈ alkyl; if present, each R⁴ is H; ifpresent, each R⁴ is independently H, halo, unsubstituted C₁-C₄ alkyl,C₁-C₄ perhaloalkyl or a substituted or unsubstituted aryl; if present,each R⁴ is independently H, halo, methyl, trifluoromethyl orcyclopropyl; X⁷, X⁸, X⁹ and X¹⁰ are taken together to provide anaromatic moiety selected from the group consisting of:

wherein each R⁴ is independently hydroxyl, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈ alkoxy, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, alkylsulfonylamino or acyl; X⁷, X⁸, X⁹ and X¹⁰ aretaken together provide an aromatic moiety selected from the groupconsisting of:

wherein R⁴ is hydroxyl, halo, C₁-C₈ perhaloalkyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,C₁-C₈ alkoxy, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino,alkylsulfonylamino or acyl; if present, each R⁴ is independently halo,unsubstituted C₁-C₄ alkyl or C₁-C₄ perhaloalkyl; R¹ is H, substituted orunsubstituted C₁-C₈ alkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl; R¹ is a substituted or unsubstituted C₁-C₈ alkyl, acyl,acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl orsubstituted or unsubstituted aryl; R¹ is methyl, ethyl, cyclopropyl,propylate, trifluoromethyl, isopropyl, tert-butyl, sec-butyl,2-methylbutyl, propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal,2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl,cyclopentyl, cyclohexyl, substituted phenyl, piperidin-4-yl,hydroxycyclopent-3-yl, hydroxycyclopent-2-yl, hydroxycycloprop-2-yl,1-hydroxy-1-methylcycloprop-2-yl, or1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl; each R^(2a) and R^(2b) isindependently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano,nitro or R^(2a) and R^(2b) are taken together to form a carbonyl moiety;and each R^(3a) and R^(3b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano or nitro; each R^(2a) and R^(2b)is independently H, unsubstituted C₁-C₈ alkyl, halo or R^(2a) and R^(2b)are taken together to form a carbonyl moiety; each R^(3a) and R^(3b) isindependently H, unsubstituted C₁-C₈ alkyl, halo or R^(3a) and R^(3b)are taken together to form a carbonyl moiety; each R^(2a) and R^(2b) isindependently H, methyl, halo or R^(2a) and R^(2b) are taken together toform a carbonyl moiety; each R^(3a) and R^(3b) is independently H,methyl, halo or R^(3a) and R^(3b) are taken together to form a carbonylmoiety; each of R^(2a), R^(2b), R^(3a) and R^(3b) is H; n at least oneof R^(2a), R^(2b), R^(3a) and R^(3b) is a substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro or is taken together with the carbon towhich it is attached and a geminal R² or R³ to form a carbonyl moiety;at least two of R^(2a), R^(2b), R^(3a) and R^(3b) is a substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, nitro or is taken together withthe carbon to which it is attached and a geminal R² or R³ to form acarbonyl moiety; at least one of R^(2a), R^(2b), R^(3a) and R^(3b) isfluoro, methyl or is taken together with the carbon to which it isattached and a geminal R² or R³ to form a carbonyl moiety; either R^(2a)and R^(2b) or R^(3a) and R^(3b) are each methyl, fluoro or are takentogether with the carbon to which it is attached and a geminal R² or R³to form a carbonyl moiety; each R^(10a), R^(10b), R^(11a) and R^(11b) isindependently H, halo, an unsubstituted C₁-C₈ alkyl, hydroxyl or R^(11a)and R^(11b) are taken together with the carbon to which they areattached to form a carbonyl or R^(11a) and R^(11b) are taken togetherwith the carbon to which they are attached to form a carbonyl; eachR^(10a), R^(10b), R^(11a) and R^(11b) is independently H, halo, anunsubstituted C₁-C₄ alkyl, hydroxyl or R^(11a) and R^(11b) are takentogether with the carbon to which they are attached to form a carbonylor R^(11a) and R^(11b) are taken together with the carbon to which theyare attached to form a carbonyl; each R^(10a), R^(10b), R^(11a) andR^(11b) is independently H, bromo, methyl, hydroxyl or R^(10a) andR^(10b) are taken together with the carbon to which they are attached toform a carbonyl or R^(11a) and R^(11b) are taken together with thecarbon to which they are attached to form a carbonyl; at least one ofR¹⁰, R^(10b), R^(11a) and R^(11b) is an unsubstituted C₁-C₈ alkyl,hydroxyl, halo or R^(10a) and R^(10b) are taken together with the carbonto which they are attached to form a carbonyl or R^(11a) and R^(11b) aretaken together with the carbon to which they are attached to form acarbonyl; at least one of R¹⁰, R^(10b), R^(11a) and R^(11b) is methyl,bromo, hydroxyl or R^(10a) and R^(10b) are taken together with thecarbon to which they are attached to form a carbonyl or R^(11a) andR^(11b) are taken together with the carbon to which they are attached toform a carbonyl; both R^(10a) and R^(10b) are methyl or both R^(11a) andR^(11b) are methyl; R^(10a) and R^(10b) are taken together with thecarbon to which they are attached to form a carbonyl or R^(11a) andR^(11b) are taken together with the carbon to which they are attached toform a carbonyl; R^(10a) is H and R^(10b) is methyl or bromo; the carbonbearing R^(10a) and R^(10b) is in the R configuration or the Sconfiguration; R^(11a) is H and R^(11b) is methyl; the carbon bearingR^(11a) and R^(11b) is in the R configuration or the S configuration;R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(11a) and R^(11b) aretaken together to form a ring selected from the group consisting of:

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, unsubstituted C₁-C₄ alkyl or is taken together with thecarbon to which it is attached and a geminal R₈ to form a cycloalkylmoiety; each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) isindependently H, hydroxyl, methyl or is taken together with the carbonto which it is attached and a geminal R₈ to form a cyclopropyl moiety;at least one of R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) istaken together with a geminal R⁸ to form a methylene or a substitutedmethylene; at least one of R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) andR^(8f) is taken together with a vicinal R⁸ to form a bond; q is 0 and mis 1; q and m are both 0; q, m, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e)and R^(8f) are taken together to form a moiety selected from the groupconsisting of:

R¹ is a substituted or unsubstituted C₁-C₈ alkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl or substitutedor unsubstituted aryl; each R^(2a) and R^(2b) is independently H,methyl, fluoro or R^(2a) and R^(2b) are taken together to form acarbonyl moiety; each R^(3a) and R^(3b) is independently H or fluoro;each R^(10a) and R^(10b) is independently H, fluoro or methyl or R^(10a)and R^(10b) are taken together to form a carbonyl; each R^(11a) andR^(11b) is independently H, fluoro or methyl or R^(10a) and R^(10b) aretaken together to form a carbonyl; Q is a substituted or unsubstitutedaryl; Q is a substituted or unsubstituted pyridyl, phenyl, pyrimidinyl,pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group; Q is asubstituted or unsubstituted phenyl or pyridyl group; Q is a phenyl orpyridyl group substituted with at least one methyl group; Q is apyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolylor thiophenyl group substituted with at least one substituted orunsubstituted C₁-C₈ alkyl, halo or perhaloalkyl moiety; Q is asubstituted or unsubstituted cycloalkyl or a substituted orunsubstituted heterocyclyl; Q is a substituted or unsubstituted pyridyl,phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group; Qis a pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl orthiomorpholinyl group substituted with at least one methyl or halogroup; Q is an unsubstituted cycloalkyl or an unsubstitutedheterocyclyl; Q is a substituted or unsubstituted cyclohexyl,morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinylmoiety; Q is a substituted cyclohexyl, morpholinyl, piperazinyl,thiomorpholinyl, cyclopentyl or pyrrolidinyl moiety substituted with atleast one carbonyl, hydroxymethyl, methyl or hydroxyl group; Q isselected from the group consisting of:

wherein each R⁹ is independently a halo, cyano, nitro, perhaloalkyl,perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstitutedheterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino,sulfonylamino, sulfonyl, aminoacyl or aminocarbonylamino; Q issubstituted with no more than one R⁹ group; Q is substituted with onlyone R⁹ group; Q is selected from the group consisting of:

and wherein R⁹ is connected to Q ortho or para to the position at whichQ is connected to the carbon bearing R^(8e) and R^(8f); Q is

andR⁹ is connected to Q para to the position at which Q is connected to thecarbon bearing R^(8e) and R^(8f);Q is substituted with two R⁹ groups; Q is selected from the groupconsisting of:

wherein each R⁹ is independently a halo, cyano, nitro, perhaloalkyl,perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,acyl, acyloxy, carbonylalkoxy, thioalkyl, alkoxy, substituted orunsubstituted amino, acylamino, sulfonylamino, sulfonyl, aminoacyl oraminocarbonylamino; Q is substituted with no more than one R⁹ group; Qis substituted with only one R⁹ group; Q is substituted with two R⁹groups; each R⁹ is independently a substituted or unsubstituted C₁-C₄alkyl, halo, trifluoromethyl or hydroxyl; each R⁹ is independentlymethyl, —CH₂OH, isopropyl, halo, trifluoromethyl or hydroxyl; Q isselected from the group consisting of:

Q is selected from the group consisting of:

Q is selected from the group consisting of:

Q is substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy or acylamino; Q is selected from thegroup consisting of:

R¹ is an unsubstituted alkyl;R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b), R^(11a) and R^(11b)are each H; each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CH; eachR^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independently H,C₁-C₄ alkyl or hydroxyl; Q is a substituted or unsubstituted aryl; R¹ isan unsubstituted alkyl; R^(2a), R^(2b), R^(3a), R^(3b), R^(10a),R^(10b), R^(11a) and R^(11b) are each H; each X⁷, X⁸, X⁹ and X¹⁰ isindependently N or CH; each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) andR^(8f) is independently H or C₁-C₄ alkyl or is taken together with ageminal R⁸ to form a methylene or a substituted methylene; Q is asubstituted or unsubstituted aryl; at least one of R^(8a), R^(8b),R^(8c), R^(8d), R^(8e) and R^(8f) is taken together with a geminal R⁸ toform a methylene or a substituted methylene; R^(2a), R^(2b), R^(3a),R^(3b), R^(10a), R^(10b), R^(11a) and R^(11b) are each H; each X⁷, X⁸,X⁹ and X¹⁰ is independently N or CH; each R^(8a), R^(8b), R^(8c),R^(8d), R^(8e) and R^(8f) is independently H or C₁-C₄ alkyl or is takentogether with a vicinal R⁸ to form a bond; Q is a substituted orunsubstituted aryl; at least one of R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) is taken together with a vicinal R⁸ to form a bond; Qis a substituted or unsubstituted phenyl or pyridyl group; Q is a phenylor pyridyl group substituted with at least one methyl group; R¹ is asubstituted or unsubstituted C₁-C₈ alkyl, acyl, acyloxy, carbonylalkoxy,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl; each R^(2a) and R^(2b) is independently H, unsubstituted C₁-C₈alkyl or halo; each R^(3a) and R^(3b) is independently H or halo; eachX⁷, X⁸, X⁹ and X¹⁰ is CR⁴; each R^(10a), R^(10b), R^(11a) and R^(11b) isindependently H or methyl; Q is a substituted or unsubstituted aryl; Qis a substituted or unsubstituted pyridyl, phenyl, pyrimidinyl,pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group; Q is apyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolylor thiophenyl group substituted with at least one substituted orunsubstituted C₁-C₈ alkyl, halo or perhaloalkyl moiety; R⁴ is H, halo,pyridyl, methyl or trifluoromethyl; R¹ is propylate, methyl, ethyl,cyclopropyl, trifluoromethyl, isopropyl, tert-butyl, sec-butyl,2-methylbutyl, propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal,2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl,cyclopentyl, cyclohexyl, substituted phenyl, piperidin-4-yl,hydroxycyclopent-3-yl, hydroxycyclopent-2-yl, hydroxycycloprop-2-yl,1-hydroxy-1-methylcycloprop-2-yl, or1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl; each R^(2a), R^(2b), R^(3a)and R^(3b) is independently H or halo; each R^(10a), R^(10b), R^(11a),R^(11b) is independently H or methyl; each R⁴ is independently H, halo,C₁-C₈ perhaloalkyl, substituted or an unsubstituted C₁-C₈ alkyl; eachR^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is H; Q is asubstituted or unsubstituted cyclohexyl, morpholinyl, piperazinyl,thiomorpholinyl, cyclopentyl or pyrrolidinyl moiety; R¹ is a methyl; atleast one of X⁷, X⁸, X⁹ and X¹⁰ is CR⁴ and each R⁴ is independently H,halo, methyl or trifluoromethyl; Q is substituted with at least onecarbonyl, hydroxymethyl, methyl or hydroxyl group; each R^(2a) andR^(2b) is independently H, a substituted or unsubstituted C₁-C₈ alkyl orR^(2a) and R^(2b) are taken together to form a carbonyl moiety; eachR^(3a) and R^(3b) is independently H, a substituted or unsubstitutedC₁-C₈ alkyl or R^(3a) and R^(3b) are taken together to form a carbonylmoiety; each R⁴ is independently H, halo or substituted or unsubstitutedC₁-C₈ alkyl; each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) isH; each R^(10a) and R^(10b) is independently H, halo, a substituted orunsubstituted C₁-C₈ alkyl or R^(10a) and R^(10b) are taken together toform a carbonyl (═O); each R^(11a) and R^(11b) is independently H, halo,a substituted or unsubstituted C₁-C₈ alkyl or R^(11a) and R^(11b) aretaken together to form a carbonyl (═O); Q is a substituted orunsubstituted pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl orthiomorpholinyl group; Q is a pyridyl, phenyl, pyrazinyl, piperazinyl,pyrrolidinyl or thiomorpholinyl group substituted with at least onemethyl or halo group; at least one of X⁷, X⁸, X⁹ and X¹⁰ is CR⁴ and eachR⁴ is independently H, halo or methyl.

Method of modulating a histamine receptor in an individual are provided,comprising administering to an individual in need thereof a compound asdetailed herein.

A pharmaceutical composition comprising a compound as detailed hereinand a pharmaceutically acceptable carrier are also provided.

Kits are also described, such as kits comprising a compound as detailedherein and instructions for use.

Methods of treating a cognitive disorder or a disorder characterized bycausing at least one symptom associated with impaired cognition are alsoprovided, comprising administering to an individual in need thereof alow dose of a compound as detailed herein, or a pharmaceuticallyacceptable salt thereof. A method of treating (i) a psychotic disorder,(ii) a psychotic disorder in an individual who is also in need ofimproved cognition or (iii) a disorder characterized by causing at leastone psychotic symptom and at least one symptom associated with impairedcognition is also provided comprising administering to an individual inneed thereof a high dose of a compound as detailed herein, or apharmaceutically acceptable salt thereof. Use of a low dose of acompound as detailed herein, or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for the treatment of acognitive disorder or a disorder characterized by causing at least onesymptom associated with impaired cognition is also provided. Use of ahigh dose of a compound as detailed herein, or a pharmaceuticallyacceptable salt thereof in the manufacture of a medicament for thetreatment of a (i) psychotic disorder, (ii) a psychotic disorder in anindividual who is also in need of improved cognition or (iii) a disordercharacterized by causing at least one psychotic symptom and at least onesymptom associated with impaired cognition is also provided. In oneinstance, a kit comprising a low dose of a compound and instructions forachieving a procognitive effect in the treatment of a cognitive disorderor a disorder characterized by causing at least one symptom associatedwith impaired cognition is provided. In another, a kit comprising a highdose of a compound as detailed herein or a pharmaceutically acceptablesalt thereof, and instructions for achieving (i) a procognitive effectin the treatment of a cognitive disorder or a disorder characterized bycausing at least one symptom associated with impaired cognition and (ii)an antipsychotic effect in the treatment of a psychotic disorder; apsychotic disorder in an individual who is also in need of improvedcognition or a disorder characterized by causing at least one psychoticsymptom and at least one symptom associated with impaired cognition isprovided.

DETAILED DESCRIPTION OF THE INVENTION Definitions

For use herein, unless clearly indicated otherwise, use of the terms“a”, “an” and the like refers to one or more.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X”.

Unless clearly indicated otherwise, “an individual” as used hereinintends a mammal, including but not limited to a human.

As used herein, the term “aminergic G protein-coupled receptors” refersto a family of transmembrane proteins involved in cellularcommunication. Aminergic G protein coupled receptors are activated bybiogenic amines and represent a subclass of the superfamily of G proteincoupled receptors, which are structurally characterized by seventransmembrane helices. Aminergic G protein-coupled receptors include butare not limited to adrenergic receptors, serotonin receptors, dopaminereceptors, histamine receptors and imidazoline receptors.

As used herein, the term “adrenergic receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toan adrenergic receptor or reduces or eliminates or increases or enhancesor mimics an activity of an adrenergic receptor. As such, an “adrenergicreceptor modulator” encompasses both an adrenergic receptor antagonistand an adrenergic receptor agonist. In some aspects, the adrenergicreceptor modulator binds to or inhibits binding to a ligand to anα₁-adrenergic receptor (e.g., α_(1A), α_(1B) and/or α_(1D)) and/or aα₂-adrenergic receptor (e.g., α_(2A), α_(2B) and/or α_(2C)) and/orreduces or eliminates or increases or enhances or mimics an activity ofa α₁-adrenergic receptor (e.g., α_(1A), α_(1B) and/or α_(1D)) and/or aα₂-adrenergic receptor (e.g., α_(2A), α_(2B) and/or α_(2C)) in areversible or irreversible manner. In some aspects, the adrenergicreceptor modulator inhibits binding of a ligand by at least about orabout any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or100% as determined in the assays described herein. In some aspects, theadrenergic receptor modulator reduces an activity of an adrenergicreceptor by at least or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90%, 95% or 100% as compared to the corresponding activity in thesame subject prior to treatment with the adrenergic receptor modulatoror compared to the corresponding activity in other subjects notreceiving the adrenergic receptor modulator. In some aspects, theadrenergic receptor modulator enhances an activity of an adrenergicreceptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% or more ascompared to the corresponding activity in the same subject prior totreatment with the adrenergic receptor modulator or compared to thecorresponding activity in other subjects not receiving the adrenergicreceptor modulator. In some aspects, the adrenergic receptor modulatoris capable of binding to the active site of an adrenergic receptor(e.g., a binding site for a ligand). In some embodiments, the adrenergicreceptor modulator is capable of binding to an allosteric site of anadrenergic receptor.

As used herein, the term “dopamine receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toa dopamine receptor or reduces or eliminates or increases or enhances ormimics an activity of a dopamine receptor. As such, a “dopamine receptormodulator” encompasses both a dopamine receptor antagonist and adopamine receptor agonist. In some aspects, the dopamine receptormodulator binds to or inhibits binding of a ligand to a dopamine-1 (D₁)and/or a dopamine-2 (D₂) receptor or reduces or eliminates or increasesor enhances or mimics an activity of a dopamine-1 (D₁) and/or adopamine-2 (D₂) receptor in a reversible or irreversible manner.Dopamine D₂ receptors are divided into two categories, D_(2L) andD_(2S), which are formed from a single gene by differential splicing.D_(2L) receptors have a longer intracellular domain than D_(2S). In someembodiments, the dopamine receptor modulator inhibits binding of aligand by at least about or about any one of 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 95% or 100% as determined in the assays describedherein. In some embodiments, the dopamine receptor modulator reduces anactivity of a dopamine receptor by at least about or about any of 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to thecorresponding activity in the same subject prior to treatment with thedopamine receptor modulator or compared to the corresponding activity inother subjects not receiving the dopamine receptor modulator. In someembodiments, the dopamine receptor modulator enhances an activity of adopamine receptor by at least about or about any of 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% ormore as compared to the corresponding activity in the same subject priorto treatment with the dopamine receptor modulator or compared to thecorresponding activity in other subjects not receiving the dopaminereceptor modulator. In some embodiments, the dopamine receptor modulatoris capable of binding to the active site of a dopamine receptor (e.g., abinding site for a ligand). In some embodiments, the dopamine receptormodulator is capable of binding to an allosteric site of a dopaminereceptor.

As used herein, the term “serotonin receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toa serotonin receptor or reduces or eliminates or increases or enhancesor mimics an activity of a serotonin receptor. As such, a “serotoninreceptor modulator” encompasses both a serotonin receptor antagonist anda serotonin receptor agonist. In some embodiments, the serotoninreceptor modulator binds to or inhibits binding of a ligand to a5-HT_(1A) and/or a 5-HT_(1B) and/or a 5-HT_(2A) and/or a 5-HT_(2B)and/or a 5-HT_(2C) and/or a 5-HT₃ and/or a 5-HT₄ and/or a 5-HT₆ and/or a5-HT₇ receptor or reduces or eliminates or increases or enhances ormimics an activity of a 5-HT_(1A) and/or a 5-HT_(1B) and/or a 5-HT_(2A)and/or a 5-HT_(2B) and/or a 5-HT_(2C) and/or a 5-HT₃ and/or a 5-HT₄and/or a 5-HT₆ and/or a 5-HT₇ receptor in a reversible or irreversiblemanner. In some embodiments, the serotonin receptor modulator inhibitsbinding of a ligand by at least about or about any one of 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as determined in the assaysdescribed herein. In some embodiments, the serotonin receptor modulatorreduces an activity of a serotonin receptor by at least about or aboutany of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% ascompared to the corresponding activity in the same subject prior totreatment with the serotonin receptor modulator or compared to thecorresponding activity in other subjects not receiving the serotoninreceptor modulator. In some embodiments, the serotonin receptormodulator enhances an activity of a serotonin receptor by at least aboutor about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100or 200% or 300% or 400% or 500% or more as compared to the correspondingactivity in the same subject prior to treatment with the serotoninreceptor modulator or compared to the corresponding activity in othersubjects not receiving the serotonin receptor modulator. In someembodiments, the serotonin receptor modulator is capable of binding tothe active site of a serotonin receptor (e.g., a binding site for aligand). In some embodiments, the serotonin receptor modulator iscapable of binding to an allosteric site of a serotonin receptor.

As used herein, the term “histamine receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toa histamine receptor or reduces or eliminates or increases or enhancesor mimics an activity of a histamine receptor. As such, a “histaminereceptor modulator” encompasses both a histamine receptor antagonist anda histamine receptor agonist. In some embodiments, the histaminereceptor modulator binds to or inhibits binding of a ligand to ahistamine H₁ and/or H₂ and/or H₃ receptor or reduces or eliminates orincreases or enhances or mimics an activity of a histamine H₁ and/or H₂and/or H₃ receptor in a reversible or irreversible manner. In someembodiments, the histamine receptor modulator inhibits binding of aligand by at least about or about any one of 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 95% or 100% as determined in the assays describedherein. In some embodiments, the histamine receptor modulator reduces anactivity of a histamine receptor by at least about or about any of 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to thecorresponding activity in the same subject prior to treatment with thehistamine receptor modulator or compared to the corresponding activityin other subjects not receiving the histamine receptor modulator. Insome embodiments, the histamine receptor modulator enhances an activityof a histamine receptor by at least about or about any of 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500%or more as compared to the corresponding activity in the same subjectprior to treatment with the histamine receptor modulator or compared tothe corresponding activity in other subjects not receiving the histaminereceptor modulator. In some embodiments, the histamine receptormodulator is capable of binding to the active site of a histaminereceptor (e.g., a binding site for a ligand). In some embodiments, thehistamine receptor modulator is capable of binding to an allosteric siteof a histamine receptor.

Unless clearly indicated otherwise, “an individual” as used hereinintends a mammal, including but not limited to a human, bovine, primate,equine, canine, feline, porcine, and ovine animals. Thus, the inventionfinds use in both human medicine and in the veterinary context,including use in agricultural animals and domestic pets. The individualmay be a human who has been diagnosed with or is suspected of having acognitive disorder, a psychotic disorder, a neurotransmitter-mediateddisorder and/or a neuronal disorder. The individual may be a human whoexhibits one or more symptoms associated with a cognitive disorder, apsychotic disorder, a neurotransmitter-mediated disorder and/or aneuronal disorder. The individual may be a human who has a mutated orabnormal gene associated with a cognitive disorder, a psychoticdisorder, a neurotransmitter-mediated disorder and/or a neuronaldisorder. The individual may be a human who is genetically or otherwisepredisposed to developing a cognitive disorder, a psychotic disorder, aneurotransmitter-mediated disorder and/or a neuronal disorder.

As used herein, “treatment” or “treating” is an approach for obtaining abeneficial or desired result, such as a clinical result. For purposes ofthis invention, beneficial or desired clinical results include, but arenot limited to, alleviation of a symptom and/or diminishment of theextent of a symptom and/or preventing a worsening of a symptomassociated with a disease or condition. In one variation, beneficial ordesired clinical results include, but are not limited to, alleviation ofa symptom and/or diminishment of the extent of a symptom and/orpreventing a worsening of a symptom associated with a cognitivedisorder, a psychotic disorder, a neurotransmitter-mediated disorderand/or a neuronal disorder. Preferably, treatment of a disease orcondition with a compound of the invention or a pharmaceuticallyacceptable salt thereof is accompanied by no or fewer side effects thanare associated with currently available therapies for the disease orcondition and/or improves the quality of life of the individual.

As used herein, “delaying” development of a disease or condition meansto defer, hinder, slow, retard, stabilize and/or postpone development ofthe disease or condition. This delay can be of varying lengths of time,depending on the history of the disease and/or individual being treated.As is evident to one skilled in the art, a sufficient or significantdelay can, in effect, encompass prevention, in that the individual doesnot develop the disease or condition. For example, a method that“delays” development of Alzheimer's disease is a method that reducesprobability of disease development in a given time frame and/or reducesextent of the disease in a given time frame, when compared to not usingthe method. Such comparisons are typically based on clinical studies,using a statistically significant number of subjects. For example,Alzheimer's disease development can be detected using standard clinicaltechniques, such as routine neurological examination, patient interview,neuroimaging, detecting alterations of levels of specific proteins inthe serum or cerebrospinal fluid (e.g., amyloid peptides and Tau),computerized tomography (CT) or magnetic resonance imaging (MRI).Similar techniques are known in the art for other diseases andconditions. Development may also refer to disease progression that maybe initially undetectable and includes occurrence, recurrence and onset.

As used herein, an “at risk” individual is an individual who is at riskof developing a cognitive disorder, a psychotic disorder, aneurotransmitter-mediated disorder and/or a neuronal disorder that canbe treated with a compound of the invention. An individual “at risk” mayor may not have a detectable disease or condition, and may or may nothave displayed detectable disease prior to the treatment methodsdescribed herein. “At risk” denotes that an individual has one or moreso-called risk factors, which are measurable parameters that correlatewith development of a disease or condition and are known in the art. Anindividual having one or more of these risk factors has a higherprobability of developing the disease or condition than an individualwithout these risk factor(s). These risk factors include, but are notlimited to, age, sex, race, diet, history of previous disease, presenceof precursor disease, genetic (i.e., hereditary) considerations, andenvironmental exposure. For example, individuals at risk for Alzheimer'sdisease include, e.g., those having relatives who have experienced thisdisease and those whose risk is determined by analysis of genetic orbiochemical markers. Genetic markers of risk for Alzheimer's diseaseinclude mutations in the APP gene, particularly mutations at position717 and positions 670 and 671 referred to as the Hardy and Swedishmutations, respectively (Hardy, Trends Neurosci., 20:154-9, 1997). Othermarkers of risk are mutations in the presenilin genes (e.g., PS1 orPS2), ApoE4 alleles, family history of Alzheimer's disease,hypercholesterolemia and/or atherosclerosis. Other such factors areknown in the art for other diseases and conditions.

As used herein, the term “pro-cognitive” includes but is not limited toan improvement of one or more mental processes such as memory,attention, perception and/or thinking, which may be assessed by methodsknown in the art.

As used herein, the term “neurotrophic” effects includes but is notlimited to effects that enhance neuron function such as growth, survivaland/or neurotransmitter synthesis.

As used herein, the term “cognitive disorders” refers to and intendsdiseases and conditions that are believed to involve or be associatedwith or do involve or are associated with progressive loss of structureand/or function of neurons, including death of neurons, and where acentral feature of the disorder may be the impairment of cognition(e.g., memory, attention, perception and/or thinking). These disordersinclude pathogen-induced cognitive dysfunction, e.g. HIV associatedcognitive dysfunction and Lyme disease associated cognitive dysfunction.Examples of cognitive disorders include Alzheimer's Disease,Huntington's Disease, Parkinson's Disease, schizophrenia, amyotrophiclateral sclerosis (ALS), autism, ADD, ADHD, mild cognitive impairment(MCI), stroke, traumatic brain injury (TBI) and age-associated memoryimpairment (AAMI).

As used herein, the term “psychotic disorders” refers to and intendsmental diseases or conditions that are believed to cause or do causeabnormal thinking and perceptions. Psychotic disorders are characterizedby a loss of reality which may be accompanied by delusions,hallucinations (perceptions in a conscious and awake state in theabsence of external stimuli which have qualities of real perception, inthat they are vivid, substantial, and located in external objectivespace), personality changes and/or disorganized thinking. Other commonsymptoms include unusual or bizarre behavior, as well as difficulty withsocial interaction and impairment in carrying out the activities ofdaily living. Exemplary psychotic disorders are schizophrenia, bipolardisorders, psychosis, anxiety and depression.

As used herein, the term “neurotransmitter-mediated disorders” refers toand intends diseases or conditions that are believed to involve or beassociated with or do involve or are associated with abnormal levels ofneurotransmitters such as histamine, serotonin, dopamine, norepinephrineor impaired function of aminergic G protein-coupled receptors. Exemplaryneurotransmitter-mediated disorders include spinal cord injury, diabeticneuropathy, allergic diseases and diseases involving geroprotectiveactivity such as age-associated hair loss (alopecia), age-associatedweight loss and age-associated vision disturbances (cataracts). Abnormalneurotransmitter levels are associated with a wide variety of diseasesand conditions including, but not limited, to Alzheimer's disease,Parkinson's Disease, autism, ADD, ADHD, Guillain-Barré syndrome, mildcognitive impairment, schizophrenia, anxiety, multiple sclerosis,stroke, traumatic brain injury, spinal cord injury, diabetic neuropathy,fibromyalgia, bipolar disorders, psychosis, depression and a variety ofallergic diseases.

As used herein, the term “neuronal disorders” refers to and intendsdiseases or conditions that are believed to involve, or be associatedwith, or do involve or are associated with neuronal cell death and/orimpaired neuronal function or decreased neuronal function. Exemplaryneuronal indications include neurodegenerative diseases and disorderssuch as Alzheimer's disease, Huntington's disease, amyotrophic lateralsclerosis (ALS), Parkinson's disease, canine cognitive dysfunctionsyndrome (CCDS), Lewy body disease, Menkes disease, Wilson disease,Creutzfeldt-Jakob disease, Fahr disease, an acute or chronic disorderinvolving cerebral circulation, such as ischemic or hemorrhagic strokeor other cerebral hemorrhagic insult, age-associated memory impairment(AAMI), mild cognitive impairment (MCI), injury-related mild cognitiveimpairment (MCI), post-concussion syndrome, post-traumatic stressdisorder, adjuvant chemotherapy, traumatic brain injury (TBI), neuronaldeath mediated ocular disorder, macular degeneration, age-relatedmacular degeneration, autism, including autism spectrum disorder,Asperger syndrome, and Rett syndrome, an avulsion injury, a spinal cordinjury, myasthenia gravis, Guillain-Barré syndrome, multiple sclerosis,diabetic neuropathy, fibromyalgia, neuropathy associated with spinalcord injury, schizophrenia, bipolar disorder, psychosis, anxiety ordepression.

As used herein, the term “neuron” represents a cell of ectodermalembryonic origin derived from any part of the nervous system of ananimal. Neurons express well-characterized neuron-specific markers,including neurofilament proteins, NeuN (Neuronal Nuclei marker), MAP2,and class III tubulin. Included as neurons are, for example,hippocampal, cortical, midbrain dopaminergic, spinal motor, sensory,sympathetic, septal cholinergic, and cerebellar neurons.

As used herein, the term “neurite outgrowth” or “neurite activation”refers to the extension of existing neuronal processes (e.g., axons anddendrites) and the growth or sprouting of new neuronal processes (e.g.,axons and dendrites). Neurite outgrowth or neurite activation may alterneural connectivity, resulting in the establishment of new synapses orthe remodeling of existing synapses.

As used herein, the term “neurogenesis” refers to the generation of newnerve cells from undifferentiated neuronal progenitor cells, also knownas multipotential neuronal stem cells. Neurogenesis actively producesnew neurons, astrocytes, glia, Schwann cells, oligodendrocytes and/orother neural lineages. Much neurogenesis occurs early in humandevelopment, though it continues later in life, particularly in certainlocalized regions of the adult brain.

As used herein, the term “neural connectivity” refers to the number,type, and quality of connections (“synapses”) between neurons in anorganism. Synapses form between neurons, between neurons and muscles (a“neuromuscular junction”), and between neurons and other biologicalstructures, including internal organs, endocrine glands, and the like.Synapses are specialized structures by which neurons transmit chemicalor electrical signals to each other and to non-neuronal cells, muscles,tissues, and organs. Compounds that affect neural connectivity may do soby establishing new synapses (e.g., by neurite outgrowth or neuriteactivation) or by altering or remodeling existing synapses. Synapticremodeling refers to changes in the quality, intensity or type of signaltransmitted at particular synapses.

As used herein, the term “neuropathy” refers to a disorder characterizedby altered function and/or structure of motor, sensory, and autonomicneurons of the nervous system, initiated or caused by a primary lesionor other dysfunction of the nervous system. Patterns of peripheralneuropathy include polyneuropathy, mononeuropathy, mononeuritismultiplex and autonomic neuropathy. The most common form is(symmetrical) peripheral polyneuropathy, which mainly affects the feetand legs. A radiculopathy involves spinal nerve roots, but if peripheralnerves are also involved the term radiculoneuropathy is used. The formof neuropathy may be further broken down by cause, or the size ofpredominant fiber involvement, e.g. large fiber or small fiberperipheral neuropathy. Central neuropathic pain can occur in spinal cordinjury, multiple sclerosis, and some strokes, as well as fibromyalgia.Neuropathy may be associated with varying combinations of weakness,autonomic changes and sensory changes. Loss of muscle bulk orfasciculations, a particular fine twitching of muscle may also be seen.Sensory symptoms encompass loss of sensation and “positive” phenomenaincluding pain. Neuropathies are associated with a variety of disorders,including diabetes (e.g., diabetic neuropathy), fibromyalgia, multiplesclerosis, and herpes zoster infection, as well as with spinal cordinjury and other types of nerve damage.

As used herein, the term “Alzheimer's disease” refers to a degenerativebrain disorder characterized clinically by progressive memory deficits,confusion, behavioral problems, inability to care for oneself, gradualphysical deterioration and, ultimately, death. Histologically, thedisease is characterized by neuritic plaques, found primarily in theassociation cortex, limbic system and basal ganglia. The majorconstituent of these plaques is amyloid beta peptide (Aβ), which is thecleavage product of beta amyloid precursor protein (βAPP or APP). APP isa type I transmembrane glycoprotein that contains a large ectopicN-terminal domain, a transmembrane domain and a small cytoplasmicC-terminal tail. Alternative splicing of the transcript of the singleAPP gene on chromosome 21 results in several isoforms that differ in thenumber of amino acids. A13 appears to have a central role in theneuropathology of Alzheimer's disease. Familial forms of the diseasehave been linked to mutations in APP and the presenilin genes (Tanzi etal., 1996, Neurobiol. Dis., 3:159-168; Hardy, 1996, Ann. Med.,28:255-258). Diseased-linked mutations in these genes result inincreased production of the 42-amino acid form of Aβ, the predominantform found in amyloid plaques. Mitochondrial dysfunction has also beenreported to be an important component of Alzheimer's disease (Bubber etal., Mitochondrial abnormalities in Alzheimer brain: MechanisticImplications, Ann Neurol., 2005, 57(5), 695-703; Wang et al., Insightsinto amyloid-β-induced mitochondrial dysfunction in Alzheimer disease,Free Radical Biology & Medicine, 2007, 43, 1569-1573; Swerdlow et al.,Mitochondria in Alzheimer's disease, Int. Rev. Neurobiol., 2002, 53,341-385; and Reddy et al., Are mitochondria critical in the pathogenesisof Alzheimer's disease?, Brain Res Rev. 2005, 49(3), 618-32). It hasbeen proposed that mitochondrial dysfunction has a causal relationshipwith neuronal function (including neurotransmitter synthesis andsecretion) and viability. Compounds which stabilize mitochondria maytherefore have a beneficial impact on Alzheimer's patients.

As used herein, the term “Huntington's disease” refers to a fatalneurological disorder characterized clinically by symptoms such asinvoluntary movements, cognition impairment or loss of cognitivefunction and a wide spectrum of behavioral disorders. Common motorsymptoms associated with Huntington's disease include chorea(involuntary writhing and spasming), clumsiness, and progressive loss ofthe abilities to walk, speak (e.g., exhibiting slurred speech) andswallow. Other symptoms of Huntington's disease can include cognitivesymptoms such as loss of intellectual speed, attention and short-termmemory and/or behavioral symptoms that can span the range of changes inpersonality, depression, irritability, emotional outbursts and apathy.Clinical symptoms typically appear in the fourth or fifth decade oflife. Huntington's disease is a devastating and often protractedillness, with death usually occurring approximately 10-20 years afterthe onset of symptoms. Huntington's disease is inherited through amutated or abnormal gene encoding an abnormal protein called the mutanthuntingtin protein; the mutated huntingtin protein produces neuronaldegeneration in many different regions of the brain. The degenerationfocuses on neurons located in the basal ganglia, structures deep withinthe brain that control many important functions including coordinatingmovement, and on neurons on the outer surface of the brain or cortex,which controls thought, perception and memory.

“Amyotrophic lateral sclerosis” or “ALS” is used herein to denote aprogressive neurodegenerative disease that affects upper motor neurons(motor neurons in the brain) and/or lower motor neurons (motor neuronsin the spinal cord) and results in motor neuron death. As used herein,the term “ALS” includes all of the classifications of ALS known in theart, including, but not limited to classical ALS (typically affectingboth lower and upper motor neurons), Primary Lateral Sclerosis (PLS,typically affecting only the upper motor neurons), Progressive BulbarPalsy (PBP or Bulbar Onset, a version of ALS that typically begins withdifficulties swallowing, chewing and speaking), Progressive MuscularAtrophy (PMA, typically affecting only the lower motor neurons) andfamilial ALS (a genetic version of ALS).

The term “Parkinson's disease” as used herein refers to any medicalcondition wherein an individual experiences one or more symptomsassociated with Parkinson's disease, such as without limitation one ormore of the following symptoms: rest tremor, cogwheel rigidity,bradykinesia, postural reflex impairment, symptoms having good responseto 1-dopa treatment, the absence of prominent oculomotor palsy,cerebellar or pyramidal signs, amyotrophy, dyspraxia and/or dysphasia.In a specific embodiment, the present invention is utilized for thetreatment of a dopaminergic dysfunction-related disorder. In a specificembodiment, the individual with Parkinson's disease has a mutation orpolymorphism in a synuclein, parkin or NURR1 nucleic acid that isassociated with Parkinson's disease. In one embodiment, the individualwith Parkinson's disease has defective or decreased expression of anucleic acid or a mutation in a nucleic acid that regulates thedevelopment and/or survival of dopaminergic neurons.

As used herein, the term “canine cognitive dysfunction syndrome,” or“CCDS” refers to an age-related deterioration of mental functiontypified by multiple cognitive impairments that affect an afflictedcanine's ability to function normally. The decline in cognitive abilitythat is associated with CCDS cannot be completely attributed to ageneral medical condition such as neoplasia, infection, sensoryimpairment, or organ failure. Diagnosis of CCDS in canines, such asdogs, is generally a diagnosis of exclusion, based on thorough behaviorand medical histories and the presence of clinical symptoms of CCDS thatare unrelated to other disease processes. Owner observation ofage-related changes in behavior is a practical means used to detect thepossible onset of CCDS in aging domestic dogs. A number of laboratorycognitive tasks may be used to help diagnose CCDS, while blood counts,chemistry panels and urinalysis can be used to rule out other underlyingdiseases that could mimic the clinical symptoms of CCDS. Symptoms ofCCDS include memory loss, which in domestic dogs may be manifested bydisorientation and/or confusion, decreased or altered interaction withfamily members and/or greeting behavior, changes in sleep-wake cycle,decreased activity level, and loss of house training or frequent,inappropriate elimination. A canine suffering from CCDS may exhibit oneor more of the following clinical or behavioral symptoms: decreasedappetite, decreased awareness of surroundings, decreased ability torecognize familiar places, people or other animals, decreased hearing,decreased ability to climb up and down stairs, decreased tolerance tobeing alone, development of compulsive behavior or repetitive behaviorsor habits, circling, tremors or shaking, disorientation, decreasedactivity level, abnormal sleep wake cycles, loss of house training,decreased or altered responsiveness to family members, and decreased oraltered greeting behavior. CCDS can dramatically affect the health andwell-being of an afflicted canine. Moreover, the companionship offeredby a pet with CCDS can become less rewarding as the severity of thedisease increases and its symptoms become more severe.

As used herein, the term “age-associated memory impairment” or “AAMI”refers to a condition that may be identified as GDS stage 2 on theglobal deterioration scale (GDS) (Reisberg, et al. (1982) Am. J.Psychiatry 139: 1136-1139) which differentiates the aging process andprogressive degenerative dementia in seven major stages. The first stageof the GDS is one in which individuals at any age have neithersubjective complaints of cognitive impairment nor objective evidence ofimpairment. These GDS stage 1 individuals are considered normal. Thesecond stage of the GDS applies to those generally elderly persons whocomplain of memory and cognitive functioning difficulties such as notrecalling names as well as they could five or ten years previously ornot recalling where they have placed things as well as they could fiveor ten years previously. These subjective complaints appear to be verycommon in otherwise normal elderly individuals. AAMI refers to personsin GDS stage 2, who may differ neurophysiologically from elderly personswho are normal and free of subjective complaints, i.e., GDS stage 1. Forexample, AAMI subjects have been found to have more electrophysiologicslowing on a computer analyzed EEG than GDS stage 1 elderly persons(Prichep, John, Ferris, Reisberg, et al. (1994) Neurobiol. Aging 15:85-90).

As used herein, the term “mild cognitive impairment” or “MCI” refers toa type of cognitive disorder characterized by a more pronounceddeterioration in cognitive functions than is typical for normalage-related decline. As a result, elderly or aged patients with MCI havegreater than normal difficulty performing complex daily tasks andlearning, but without the inability to perform normal social, everyday,and/or professional functions typical of patients with Alzheimer'sdisease, or other similar neurodegenerative disorders eventuallyresulting in dementia. MCI is characterized by subtle, clinicallymanifest deficits in cognition, memory, and functioning, amongst otherimpairments, which are not of sufficient magnitude to fulfill criteriafor diagnosis of Alzheimer's disease or other dementia. MCI alsoencompasses injury-related MCI, defined herein as cognitive impairmentresulting from certain types of injury, such as nerve injury (i.e.,battlefield injuries, including post-concussion syndrome, and the like),neurotoxic treatment (i.e., adjuvant chemotherapy resulting in “chemobrain” and the like), and tissue damage resulting from physical injuryor other neurodegeneration, which is separate and distinct from mildcognitive impairment resulting from stroke, ischemia, hemorrhagicinsult, blunt force trauma, and the like.

As used herein, the term “traumatic brain injury” or “TBI” refers to abrain injury caused by a sudden trauma, such as a blow or jolt or apenetrating head injury, which disrupts the function or damages thebrain. Symptoms of TBI can range from mild, moderate to severe and cansignificantly affect many cognitive (deficits of language andcommunication, information processing, memory, and perceptual skills),physical (ambulation, balance, coordination, fine motor skills,strength, and endurance), and psychological skills.

“Neuronal death mediated ocular disease” intends an ocular disease inwhich death of the neuron is implicated in whole or in part. The diseasemay involve death of photoreceptors. The disease may involve retinalcell death. The disease may involve ocular nerve death by apoptosis.Particular neuronal death mediated ocular diseases include but are notlimited to macular degeneration, glaucoma, retinitis pigmentosa,congenital stationary night blindness (Oguchi disease), childhood onsetsevere retinal dystrophy, Leber congenital amaurosis, Bardet-Biedlesyndrome, Usher syndrome, blindness from an optic neuropathy, Leber'shereditary optic neuropathy, color blindness and Hansen-Larson-Bergsyndrome.

As used herein, the term “macular degeneration” includes all forms andclassifications of macular degeneration known in the art, including, butnot limited to diseases that are characterized by a progressive loss ofcentral vision associated with abnormalities of Bruch's membrane, thechoroid, the neural retina and/or the retinal pigment epithelium. Theterm thus encompasses disorders such as age-related macular degeneration(ARMD) as well as rarer, earlier-onset dystrophies that in some casescan be detected in the first decade of life. Other maculopathies includeNorth Carolina macular dystrophy, Sorsby's fundus dystrophy, Stargardt'sdisease, pattern dystrophy, Best disease, and Malattia Leventinese.

As used herein, the term “autism” refers to a brain development disorderthat impairs social interaction and communication and causes restrictedand repetitive behavior, typically appearing during infancy or earlychildhood. The cognitive and behavioral defects are thought to result inpart from altered neural connectivity. Autism encompasses relateddisorders sometimes referred to as “autism spectrum disorder,” as wellas Asperger syndrome and Rett syndrome.

As used herein, the term “nerve injury” or “nerve damage” refers tophysical damage to nerves, such as avulsion injury (i.e., where a nerveor nerves have been torn or ripped) or spinal cord injury (i.e., damageto white matter or myelinated fiber tracts that carry sensation andmotor signals to and from the brain). Spinal cord injury can occur frommany causes, including physical trauma (i.e., car accidents, sportsinjuries, and the like), tumors impinging on the spinal column,developmental disorders, such as spina bifida, and the like.

As used herein, the term “myasthenia gravis” or “MG” refers to anon-cognitive neuromuscular disorder caused by immune-mediated loss ofacetylcholine receptors at neuromuscular junctions of skeletal muscle.Clinically, MG typically appears first as occasional muscle weakness inapproximately two-thirds of patients, most commonly in the extraocularmuscles. These initial symptoms eventually worsen, producing droopingeyelids (ptosis) and/or double vision (diplopia), often causing thepatient to seek medical attention. Eventually, many patients developgeneral muscular weakness that may fluctuate weekly, daily, or even morefrequently. Generalized MG often affects muscles that control facialexpression, chewing, talking, swallowing, and breathing; before recentadvances in treatment, respiratory failure was the most common cause ofdeath.

As used herein, the term “Guillain-Barré syndrome” refers to anon-cognitive disorder in which the body's immune system attacks part ofthe peripheral nervous system. The first symptoms of this disorderinclude varying degrees of weakness or tingling sensations in the legs.In many instances the weakness and abnormal sensations spread to thearms and upper body. These symptoms can increase in intensity untilcertain muscles cannot be used at all and, when severe, the patient isalmost totally paralyzed. In these cases the disorder is lifethreatening—potentially interfering with breathing and, at times, withblood pressure or heart rate—and is considered a medical emergency. Mostpatients, however, recover from even the most severe cases ofGuillain-Barré syndrome, although some continue to have a certain degreeof weakness.

As used herein, the term “multiple sclerosis” or “MS” refers to anautoimmune condition in which the immune system attacks the centralnervous system (CNS), leading to demyelination of neurons. It may causenumerous symptoms, many of which are non-cognitive, and often progressesto physical disability. MS affects the areas of the brain and spinalcord known as the white matter. White matter cells carry signals betweenthe grey matter areas, where the processing is done, and the rest of thebody. More specifically, MS destroys oligodendrocytes which are thecells responsible for creating and maintaining a fatty layer, known asthe myelin sheath, which helps the neurons carry electrical signals. MSresults in a thinning or complete loss of myelin and, less frequently,the cutting (transection) of the neuron's extensions or axons. When themyelin is lost, the neurons can no longer effectively conduct theirelectrical signals. Almost any neurological symptom can accompany thedisease. MS takes several forms, with new symptoms occurring either indiscrete attacks (relapsing forms) or slowly accumulating over time(progressive forms). Most people are first diagnosed withrelapsing-remitting MS but develop secondary-progressive MS (SPMS) aftera number of years. Between attacks, symptoms may go away completely, butpermanent neurological problems often persist, especially as the diseaseadvances.

As used herein, the term “schizophrenia” refers to a chronic, mentaldisorder characterized by one or more positive symptoms (e.g., delusionsand hallucinations) and/or negative symptoms (e.g., blunted emotions andlack of interest) and/or disorganized symptoms (e.g., disorganizedthinking and speech or disorganized perception and behavior).Schizophrenia as used herein includes all forms and classifications ofschizophrenia known in the art, including, but not limited to catatonictype, hebephrenic type, disorganized type, paranoid type, residual typeor undifferentiated type schizophrenia and deficit syndrome and/or thosedescribed in American Psychiatric Association: Diagnostic andStatistical Manual of Mental Disorders, Fourth Edition, Washington D.C.,2000 or in International Statistical Classification of Diseases andRelated Health Problems, or otherwise known to those of skill in theart.

“Cognitive impairment associated with schizophrenia” or “CIAS” includesneuropsychological deficits in attention, working memory, verballearning, and problem solving. These deficits are believed to be linkedto impairment in functional status (e.g., social behavior, workperformance, and activities of daily living).

As used herein “geroprotective activity” or “geroprotector” means abiological activity that slows down ageing and/or prolongs life and/orincreases or improves the quality of life via a decrease in the amountand/or the level of intensity of pathologies or conditions that are notlife-threatening but are associated with the aging process and which aretypical for elderly people. Pathologies or conditions that are notlife-threatening but are associated with the aging process include suchpathologies or conditions as loss of sight (cataract), deterioration ofthe dermatohairy integument (alopecia), and an age-associated decreasein weight due to the death of muscular and/or fatty cells.

As used herein, attention-deficit hyperactivity disorder (ADHD) is themost common child neuropsychiatric condition present in school-agedchildren, affecting about 5-8% of this population. ADHD refers to achronic disorder that initially manifests in childhood and ischaracterized by hyperactivity, impulsivity, and/or inattention. ADHD ischaracterized by persistent patterns of inattention and/orimpulsivity-hyperactivity that are much more extreme than is observed inindividuals at the same developmental level or stage. There isconsiderable evidence, from family and twin studies, that ADHD has asignificant genetic component. This disorder is thought to be due to aninteraction of environmental and genetic factors. ADHD includes allknown types of ADHD. For example, Diagnostic & Statistical Manual forMental Disorders (DSM-IV) identifies three subtypes of ADHD: (1) ADHD,Combined Type which is characterized by both inattention andhyperactivity-impulsivity symptoms; 2. ADHD, Predominantly InattentiveType which is characterized by inattention but nothyperactivity-impulsivity symptoms; and 3. ADHD, PredominantlyHyperactive-Impulsive Type which is characterized byHyperactivity-impulsivity but not inattention symptoms.

As used herein, attention-deficit disorder (ADD) refers to a disorder inprocessing neural stimuli that is characterized by distractibility andimpulsivity that can result in inability to control behavior and canimpair an individual's social, academic, or occupational function anddevelopment. ADD may be diagnosed by known methods, which may includeobserving behavior and diagnostic interview techniques.

As used herein “allergic disease” refers to a disorder of the immunesystem which is characterized by excessive activation of mast cells andbasophils and production of IgE immunoglobulins, resulting in an extremeinflammatory response. It represents a form of hypersensitivity to anenvironmental substance known as allergen and is an acquired disease.Common allergic reactions include eczema, hives, hay fever, asthma, foodallergies, and reactions to the venom of stinging insects such as waspsand bees. Allergic reactions are accompanied by an excessive release ofhistamines, and can thus be treated with antihistaminic agents.

As used herein, by “combination therapy” is meant a therapy thatincludes two or more different compounds. Thus, in one aspect, acombination therapy comprising a compound detailed herein and anothercompound is provided. In some variations, the combination therapyoptionally includes one or more pharmaceutically acceptable carriers orexcipients, non-pharmaceutically active compounds, and/or inertsubstances. In various embodiments, treatment with a combination therapymay result in an additive or even synergistic (e.g., greater thanadditive) result compared to administration of a single compound of theinvention alone. In some embodiments, a lower amount of each compound isused as part of a combination therapy compared to the amount generallyused for individual therapy. Preferably, the same or greater therapeuticbenefit is achieved using a combination therapy than by using any of theindividual compounds alone. In some embodiments, the same or greatertherapeutic benefit is achieved using a smaller amount (e.g., a lowerdose or a less frequent dosing schedule) of a compound in a combinationtherapy than the amount generally used for individual compound ortherapy. Preferably, the use of a small amount of compound results in areduction in the number, severity, frequency, and/or duration of one ormore side-effects associated with the compound.

As used herein, the term “effective amount” intends such amount of acompound of the invention which in combination with its parameters ofefficacy and toxicity, as well as based on the knowledge of thepracticing specialist should be effective in a given therapeutic form.As is understood in the art, an effective amount may be in one or moredoses, i.e., a single dose or multiple doses may be required to achievethe desired treatment endpoint. An effective amount may be considered inthe context of administering one or more therapeutic agents, and asingle agent may be considered to be given in an effective amount if, inconjunction with one or more other agents, a desirable or beneficialresult may be or is achieved. Suitable doses of any of theco-administered compounds may optionally be lowered due to the combinedaction (e.g., additive or synergistic effects) of the compounds.

As used herein, “unit dosage form” refers to physically discrete units,suitable as unit dosages, each unit containing a predetermined quantityof active ingredient calculated to produce the desired therapeuticeffect in association with the required pharmaceutical carrier. Unitdosage forms may contain a single or a combination therapy.

As used herein, the term “controlled release” refers to adrug-containing formulation or fraction thereof in which release of thedrug is not immediate, i.e., with a “controlled release” formulation,administration does not result in immediate release of the drug into anabsorption pool. The term encompasses depot formulations designed togradually release the drug compound over an extended period of time.Controlled release formulations can include a wide variety of drugdelivery systems, generally involving mixing the drug compound withcarriers, polymers or other compounds having the desired releasecharacteristics (e.g., pH-dependent or non-pH-dependent solubility,different degrees of water solubility, and the like) and formulating themixture according to the desired route of delivery (e.g., coatedcapsules, implantable reservoirs, injectable solutions containingbiodegradable capsules, and the like).

As used herein, by “pharmaceutically acceptable” or “pharmacologicallyacceptable” is meant a material that is not biologically or otherwiseundesirable, e.g., the material may be incorporated into apharmaceutical composition administered to a patient without causing anysignificant undesirable biological effects or interacting in adeleterious manner with any of the other components of the compositionin which it is contained. Pharmaceutically acceptable carriers orexcipients have preferably met the required standards of toxicologicaland manufacturing testing and/or are included on the Inactive IngredientGuide prepared by the U.S. Food and Drug administration.

“Pharmaceutically acceptable salts” are those salts which retain atleast some of the biological activity of the free (non-salt) compoundand which can be administered as drugs or pharmaceuticals to anindividual. Such salts, for example, include: (1) acid addition salts,formed with inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or formedwith organic acids such as acetic acid, oxalic acid, propionic acid,succinic acid, maleic acid, tartaric acid and the like; (2) salts formedwhen an acidic proton present in the parent compound either is replacedby a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or analuminum ion; or coordinates with an organic base. Acceptable organicbases include ethanolamine, diethanolamine, triethanolamine and thelike. Acceptable inorganic bases include aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, andthe like. Further examples of pharmaceutically acceptable salts includethose listed in Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 1977January; 66(1):1-19. Pharmaceutically acceptable salts can be preparedin situ in the manufacturing process, or by separately reacting apurified compound of the invention in its free acid or base form with asuitable organic or inorganic base or acid, respectively, and isolatingthe salt thus formed during subsequent purification. It should beunderstood that a reference to a pharmaceutically acceptable saltincludes the solvent addition forms or crystal forms thereof,particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and are oftenformed during the process of crystallization. Hydrates are formed whenthe solvent is water, or alcoholates are formed when the solvent isalcohol. Polymorphs include the different crystal packing arrangementsof the same elemental composition of a compound. Polymorphs usually havedifferent X-ray diffraction patterns, infrared spectra, melting points,density, hardness, crystal shape, optical and electrical properties,stability, and solubility. Various factors such as the recrystallizationsolvent, rate of crystallization, and storage temperature may cause asingle crystal form to dominate.

The term “excipient” as used herein means an inert or inactive substancethat may be used in the production of a drug or pharmaceutical, such asa tablet containing a compound of the invention as an active ingredient.Various substances may be embraced by the term excipient, includingwithout limitation any substance used as a binder, disintegrant,coating, compression/encapsulation aid, cream or lotion, lubricant,solutions for parenteral administration, materials for chewable tablets,sweetener or flavoring, suspending/gelling agent, or wet granulationagent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.;coatings include, e.g., cellulose acetate phthalate, ethylcellulose,gellan gum, maltodextrin, enteric coatings, etc.;compression/encapsulation aids include, e.g., calcium carbonate,dextrose, fructose dc (dc=“directly compressible”), honey dc, lactose(anhydrate or monohydrate; optionally in combination with aspartame,cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.;disintegrants include, e.g., croscarmellose sodium, gellan gum, sodiumstarch glycolate, etc.; creams or lotions include, e.g., maltodextrin,carrageenans, etc.; lubricants include, e.g., magnesium stearate,stearic acid, sodium stearyl fumarate, etc.; materials for chewabletablets include, e.g., dextrose, fructose dc, lactose (monohydrate,optionally in combination with aspartame or cellulose), etc.;suspending/gelling agents include, e.g., carrageenan, sodium starchglycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame,dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulationagents include, e.g., calcium carbonate, maltodextrin, microcrystallinecellulose, etc.

“Alkyl” refers to and includes saturated linear, branched, or cyclicunivalent hydrocarbon structures and combinations thereof. Particularalkyl groups are those having 1 to 20 carbon atoms (a “C₁-C₂₀ alkyl”).More particular alkyl groups are those having 1 to 8 carbon atoms (a“C₁-C₈ alkyl”). When an alkyl residue having a specific number ofcarbons is named, all geometric isomers having that number of carbonsare intended to be encompassed and described; thus, for example, “butyl”is meant to include n-butyl, sec-butyl, iso-butyl, tert-butyl andcyclobutyl; “propyl” includes n-propyl, iso-propyl and cyclopropyl. Thisterm is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl,cyclohexylmethyl, cyclopropyl and the like. Cycloalkyl is a subset ofalkyl and can consist of one ring, such as cyclohexyl, or multiplerings, such as adamantyl. A cycloalkyl comprising more than one ring maybe fused, spiro or bridged, or combinations thereof. A preferredcycloalkyl is a saturated cyclic hydrocarbon having from 3 to 13 annularcarbon atoms. A more preferred cycloalkyl is a saturated cyclichydrocarbon having from 3 to 8 annular carbon atoms (a “C₃-C₈cycloalkyl”). Examples of cycloalkyl groups include adamantyl,decahydronaphthalenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyland the like.

“Alkylene” refers to the same residues as alkyl, but having bivalency.Examples of alkylene include methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—) and the like.

“Alkenyl” refers to an unsaturated hydrocarbon group having at least onesite of olefinic unsaturation (i.e., having at least one moiety of theformula C═C) and preferably having from 2 to 10 carbon atoms and morepreferably 2 to 8 carbon atoms. Examples of alkenyl include but are notlimited to —CH₂—CH═CH—CH₃ and —CH₂—CH₂-cyclohexenyl, where the ethylgroup of the latter example can be attached to the cyclohexenyl moietyat any available position on the ring. Cycloalkenyl is a subset ofalkenyl and can consist of one ring, such as cyclohexyl, or multiplerings, such as norbornenyl. A more preferred cycloalkenyl is anunsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms(a “C₃-C₈ cycloalkenyl”). Examples of cycloalkenyl groups includecyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.

“Alkynyl” refers to an unsaturated hydrocarbon group having at least onesite of acetylenic unsaturation (i.e., having at least one moiety of theformula C≡C) and preferably having from 2 to 10 carbon atoms and morepreferably 3 to 8 carbon atoms.

“Substituted alkyl” refers to an alkyl group having from 1 to 5substituents including, but not limited to, substituents such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted alkenyl” refers to alkenyl group having from 1 to 5substituents s including, but not limited to, substituents such asalkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 5substituents including, but not limited to, groups such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)—, cycloalkyl-C(O)—, substitutedcycloalkyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—,substituted heteroaryl-C(O)—, heterocyclic-C(O)—, and substitutedheterocyclic-C(O)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Acyloxy” refers to the groups H—C(O)O—, alkyl-C(O)O—, substitutedalkyl-C(O)O—, alkenyl-C(O)O—, substituted alkenyl-C(O)O—,alkynyl-C(O)O—, substituted alkynyl-C(O)O—, cycloalkyl-C(O)O—,substituted cycloalkyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—,heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—, heterocyclic-C(O)O—,and substituted heterocyclic-C(O)O—, wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Heterocycle”, “heterocyclic”, or “heterocyclyl” refers to a saturatedor an unsaturated non-aromatic group having a single ring or multiplecondensed rings, and having from 1 to 10 annular carbon atoms and from 1to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen. Aheterocycle comprising more than one ring may be fused, spiro orbridged, or any combination thereof. In fused ring systems, one or moreof the rings can be aryl or heteroaryl. A heterocycle having more thanone ring where at least one ring is aromatic may be connected to theparent structure at either a non-aromatic ring position or at anaromatic ring position. In one variation, a heterocycle having more thanone ring where at least one ring is aromatic is connected to the parentstructure at a non-aromatic ring position.

“Substituted heterocyclic” or “substituted heterocyclyl” refers to aheterocycle group which is substituted with from 1 to 3 substituentsincluding, but not limited to, substituents such as alkoxy, substitutedalkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted orunsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy,substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol,thioalkyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo,carbonylalkylenealkoxy and the like. In one variation, a substitutedheterocycle is a heterocycle substituted with an additional ring,wherein the additional ring may be aromatic or non-aromatic.

“Aryl” or “Ar” refers to an unsaturated aromatic carbocyclic grouphaving a single ring (e.g., phenyl) or multiple condensed rings (e.g.,naphthyl or anthryl) which condensed rings may or may not be aromatic.In one variation, the aryl group contains from 6 to 14 annular carbonatoms. An aryl group having more than one ring where at least one ringis non-aromatic may be connected to the parent structure at either anaromatic ring position or at a non-aromatic ring position. In onevariation, an aryl group having more than one ring where at least onering is non-aromatic is connected to the parent structure at an aromaticring position.

“Heteroaryl” or “HetAr” refers to an unsaturated aromatic heterocyclicgroup having from 1 to 10 annular carbon atoms and at least one annularheteroatom, including but not limited to heteroatoms such as nitrogen,oxygen and sulfur. A heteroaryl group may have a single ring (e.g.,pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl,benzothienyl) which condensed rings may or may not be aromatic. Aheteroaryl group having more than one ring where at least one ring isnon-aromatic may be connected to the parent structure at either anaromatic ring position or at a non-aromatic ring position. In onevariation, a heteroaryl group having more than one ring where at leastone ring is non-aromatic is connected to the parent structure at anaromatic ring position.

“Substituted aryl” refers to an aryl group having 1 to 5 substituentsincluding, but not limited to, groups such as alkoxy, substitutedalkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted orunsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy,substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol,thioalkyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy andthe like.

“Substituted heteroaryl” refers to a heteroaryl group having 1 to 5substituents including, but not limited to, groups such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo,carbonylalkylenealkoxy and the like.

“Aralkyl” refers to a residue in which an aryl moiety is attached to analkyl residue and wherein the aralkyl group may be attached to theparent structure at either the aryl or the alkyl residue. Preferably, anaralkyl is connected to the parent structure via the alkyl moiety. Inone variation, an aralkyl is a fused ring system where at least onecycloalkyl moiety is fused with at least one aryl moiety. A “substitutedaralkyl” refers to a residue in which an aryl moiety is attached to asubstituted alkyl residue and wherein the aralkyl group may be attachedto the parent structure at either the aryl or the alkyl residue. When anaralkyl is connected to the parent structure via the alkyl moiety, itmay also be referred to as an “alkaryl”. More particular alkaryl groupsare those having 1 to 3 carbon atoms in the alkyl moiety (a “C₁-C₃alkaryl”).

“Alkoxy” refers to the group alkyl-O—, which includes, by way ofexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.Similarly, alkenyloxy refers to the group “alkenyl-O—” and alkynyloxyrefers to the group “alkynyl-O—”. “Substituted alkoxy” refers to thegroup substituted alkyl-O.

“Unsubstituted amino” refers to the group —NH₂.

“Substituted amino” refers to the group —NR_(a)R_(b), where either (a)each R_(a) and R_(b) group is independently selected from the groupconsisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic, providedthat both R_(a) and R_(b) groups are not H; or (b) R_(a) and R_(b) arejoined together with the nitrogen atom to form a heterocyclic orsubstituted heterocyclic ring.

“Acylamino” refers to the group —C(O)NR_(a)R_(b) where R_(a) and R_(b)are independently selected from the group consisting of H, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic or R_(a) and R_(b) groups can bejoined together with the nitrogen atom to form a heterocyclic orsubstituted heterocyclic ring.

“Aminocarbonylalkoxy” refers to the group —NR_(a)C(O)OR_(b) where eachR_(a) and R_(b) group is independently selected from the groupconsisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclyl.

“Aminoacyl” refers to the group —NR_(a)C(O)R_(b) where each R_(a) andR_(b) group is independently selected from the group consisting of H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic or substituted heterocyclic. Preferably, R_(a)is H or alkyl.

“Aminosulfonyl” refers to the groups —NRSO₂-alkyl, —NRSO₂ substitutedalkyl, —NRSO₂-alkenyl, —NRSO₂-substituted alkenyl, —NRSO₂-alkynyl,—NRSO₂-substituted alkynyl, —NRSO₂-cycloalkyl, —NRSO₂-substitutedcycloalkyl, —NRSO₂-aryl, —NRSO₂-substituted aryl, —NRSO₂-heteroaryl,—NRSO₂-substituted heteroaryl, —NRSO₂-heterocyclic, and—NRSO₂-substituted heterocyclic, where R is H or alkyl and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Sulfonylamino” refers to the groups —SO₂NH₂, —SO₂NR-alkyl,—SO₂NR-substituted alkyl, —SO₂NR-alkenyl, —SO₂NR-substituted alkenyl,—SO₂NR-alkynyl, —SO₂NR-substituted alkynyl, —SO₂NR-aryl,—SO₂NR-substituted aryl, —SO₂NR-heteroaryl, —SO₂NR-substitutedheteroaryl, —SO₂NR-heterocyclic, and —SO₂NR-substituted heterocyclic,where R is H or alkyl, or —SO₂NR₂, where the two R groups are takentogether and with the nitrogen atom to which they are attached to form aheterocyclic or substituted heterocyclic ring.

“Sulfonyl” refers to the groups —SO₂-alkyl, —SO₂-substituted alkyl,—SO₂-alkenyl, —SO₂-substituted alkenyl, —SO₂-alkynyl, —SO₂-substitutedalkynyl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl,—SO₂-substituted heteroaryl, —SO₂-heterocyclic, and —SO₂-substitutedheterocyclic.

“Carbonylalkylenealkoxy” refers to the group —C(═O)—(CH₂)_(n)—OR where Ris a substituted or unsubstituted alkyl and n is an integer from 1 to100, more preferably n is an integer from 1 to 10 or 1 to 5.

“Halo” or “halogen” refers to elements of the Group 17 series havingatomic number 9 to 85. Preferred halo groups include the radicals offluorine, chlorine, bromine and iodine. Where a residue is substitutedwith more than one halogen, it may be referred to by using a prefixcorresponding to the number of halogen moieties attached, e.g.,dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may bebut are not necessarily the same halogen; thus 4-chloro-3-fluorophenylis within the scope of dihaloaryl. An alkyl group in which each H isreplaced with a halo group is referred to as a “perhaloalkyl.” Apreferred perhaloalkyl group is trifluoromethyl (—CF₃). Similarly,“perhaloalkoxy” refers to an alkoxy group in which a halogen takes theplace of each H in the hydrocarbon making up the alkyl moiety of thealkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy(—OCF₃).

“Carbonyl” refers to the group C═O.

“Cyano” refers to the group —CN.

“Oxo” refers to the moiety ═O.

“Nitro” refers to the group —NO₂.

“Thioalkyl” refers to the groups —S-alkyl.

“Alkylsulfonylamino” refers to the groups —R¹SO₂NR_(a)R_(b) where R_(a)and R_(b) are independently selected from the group consisting of H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, or the R_(a) andR_(b) groups can be joined together with the nitrogen atom to form aheterocyclic or substituted heterocyclic ring and R¹ is an alkyl group.

“Carbonylalkoxy” refers to as used herein refers to the groups—C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl, —C(O)O-substitutedaryl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl, —C(O)O-alkynyl,—C(O)O-substituted alkynyl, —C(O)O-heteroaryl, —C(O)O-substitutedheteroaryl, —C(O)O-heterocyclic or —C(O)O-substituted heterocyclic.

“Geminal” refers to the relationship between two moieties that areattached to the same atom. For example, in the residue —CH₂—CHR¹R², R¹and R² are geminal and R¹ may be referred to as a geminal R group to R².

“Vicinal” refers to the relationship between two moieties that areattached to adjacent atoms. For example, in the residue —CHR¹—CH₂R², R¹and R² are vicinal and R¹ may be referred to as a vicinal R group to R².

A composition of “substantially pure” compound means that thecomposition contains no more than 15% or preferably no more than 10% ormore preferably no more than 5% or even more preferably no more than 3%and most preferably no more than 1% impurity, which impurity may be thecompound in a different stereochemical form. For instance, a compositionof substantially pure S compound means that the composition contains nomore than 15% or no more than 10% or no more than 5% or no more than 3%or no more than 1% of the R form of the compound.

Compounds of the Invention

Compounds according to the invention are detailed herein, including inthe Brief Summary of the Invention and the appended claims. Theinvention includes the use of all of the compounds described herein,including any and all stereoisomers, including geometric isomers(cis/trans) or E/Z isomers, salts and solvates of the compoundsdescribed herein, as histamine receptor modulators, as well as methodsof making such compounds.

The invention embraces compounds of the formula (I):

where:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy;

each R^(2a), R^(2b), R^(3a) and R^(3b) is independently H, hydroxyl,nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is takentogether with the carbon to which it is attached and a geminal R² or R³to form a cycloalkyl moiety or a carbonyl moiety;

each R^(10a), R^(10b), R^(11a) and R^(11b) is independently H, hydroxyl,nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together withthe carbon to which it is attached and a geminal R¹⁰ or R¹¹ to form acycloalkyl moiety or a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each m and q is independently 0 or 1;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, alkoxy, halo, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₂-C₈alkenyl, or is taken together with a geminal R⁸ to form a moiety of theformula —OCH₂CH₂O—, is taken together with the carbon to which it isattached and a geminal R⁸ to form a cycloalkyl moiety or a carbonylmoiety, is taken together with a geminal R⁸ to form a methylene or asubstituted methylene, is taken together with a vicinal R⁸ and thecarbon atoms to which they are attached to form a substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or istaken together with a vicinal R⁸ to form a bond, provided when an R⁸ istaken together with a vicinal R⁸ to form a bond, the geminal R⁸ is otherthan hydroxyl;

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano oralkynyl;

provided that the compound is other than a compound in Table 1;

or a salt or solvate thereof.

Compounds of the general formula (I) are described as new histaminereceptor modulators. Compounds of the invention may also find use intreating neurodegenerative diseases.

In one variation, the compounds of the invention, pharmaceuticalcompositions thereof, isolated forms thereof and methods of using andadministering the compounds detailed herein, encompass any of thecompounds of Formula (I), including those listed in Table 1 or a saltthereof.

In one variation, the compound of the formula (I) is provided, whereeach X⁷, X⁸, X⁹, X¹⁰, R¹, R^(10a), R^(10b), R^(11a), R^(11b), q and mare as defined for formula (I); each R² independently H, hydroxyl,nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is takentogether with the carbon to which it is attached and a geminal R² or R³to form a carbonyl moiety; each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e)and R^(8f) is independently H, hydroxyl, C₁-C₈ alkyl, C₁-C₈perhaloalkyl, carboxy, carbonylalkoxy, is taken together with the carbonto which it is attached and a geminal R⁸ to form a cycloalkyl moiety ora carbonyl moiety, is taken together with a geminal R⁸ to form amethylene or a substituted methylene, is taken together with a vicinalR⁸ and the carbon atoms to which they are attached to form a substitutedor unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or istaken together with a vicinal R⁸ to form a bond, provided: (i) at mostone pair of vicinal R⁸ groups are taken together to form a bond; and(ii) when an R⁸ is taken together with a vicinal R⁸ to form a bond, thegeminal R⁸ is other than hydroxyl; Q is a substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl orsubstituted or a unsubstituted heterocyclyl, unsubstituted amino,substituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy,aminocarbonylalkoxy or acylamino; provided that the compound is otherthan a compound in Table 1; or a salt or solvate thereof. In one suchvariation, the compounds, pharmaceutical compositions thereof, isolatedforms thereof and methods of using and administering the compoundsdetailed herein, encompass any of the compounds of Formula (I),including those listed in Table 1 or a salt thereof.

In another variation, the compound of the invention is of the formula(I), where each R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b),R^(11a) and R^(11b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, hydroxyl, alkoxy, cyano, nitro or is taken togetherwith the carbon to which it is attached to and a geminal R group to forma carbonyl moiety or a cycloalkyl moiety. In yet another variation, thecompound is of the formula (I), where each R^(2a), R^(2b), R^(3a) andR^(3b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, hydroxyl, alkoxy, cyano, nitro or is taken together with thecarbon to which it is attached to and a geminal R group to form acarbonyl moiety and each R^(10a), R^(10b), R^(11a) and R^(11b) isindependently H, substituted or unsubstituted C₁-C₈ alkyl or is takentogether with the carbon to which it is attached to and a geminal Rgroup to form a carbonyl moiety or a cycloalkyl moiety (e.g.cyclopropyl). In another variation, the compound is of the formula (I),where Q is a substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl or substituted or aunsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy,aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino.

The invention also embraces compounds of the formula (A):

or a salt or solvate thereof,

wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy;

each R^(2a), R^(2b), R^(3a) and R^(3b) is independently H, hydroxyl,nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is takentogether with the carbon to which it is attached and a geminal R² or R³to form a cycloalkyl moiety or a carbonyl moiety;

each R^(10a), R^(10b), R^(11a) and R^(11b) is independently H, hydroxyl,nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together withthe carbon to which it is attached and a geminal R¹⁰ or R¹¹ to form acycloalkyl moiety or a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each m and q is independently 0 or 1;

each R^(8a), R^(8b), R^(8c) and R^(8d) is independently H, hydroxyl,alkoxy, halo, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxy,carbonylalkoxy, or is taken together with a geminal R^(8(a-d)) to form amoiety of the formula —OCH₂CH₂O—, or is taken together with the carbonto which it is attached and a geminal R⁸ to form a cycloalkyl moiety ora carbonyl moiety;

each R^(8g) and R^(8h) is independently H, halo, alkoxy, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₁-C₈ alkyl,-substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₃-C₈ cycloalkyl, C₁-C₈perhaloalkyl, carboxy, or carbonylalkoxy and the

bond indicates the presence of either an E or Z double bondconfiguration, or R^(8g) and R^(8h) are taken together to form a bond;and

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano oralkynyl.

In one variation, the compound of the formula (A) is provided, whereeach X⁷, X⁸, X⁹, X¹⁰, R¹, R^(10a), R^(10b), R^(11a), R^(11b), q and mare as defined for formula (A); each R^(2a), R^(2b), R^(3a) and R^(3b)is independently H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy, or is taken together with the carbon to which itis attached and a geminal R² or R³ to form a carbonyl moiety; eachR^(8a), R^(8b), R^(8c) and R^(8d) is independently H, hydroxyl, C₁-C₈alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy, is taken togetherwith the carbon to which it is attached and a geminal R⁸ to form acycloalkyl moiety or a carbonyl moiety, is taken together with a geminalR⁸ to form a methylene or a substituted methylene; R^(8g) is H, C₁-C₈alkyl, C₃-C₈ cycloalkyl, C₁-C₈ perhaloalkyl or is taken together withR^(8h) and the carbon atoms to which they are attached to form asubstituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₃-C₈ cycloalkenyl or substituted or unsubstitutedheterocyclyl moiety and the

bond indicates the presence of either an E or Z double bondconfiguration; R^(8h) is H, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈perhaloalkyl or is taken together with R^(8g) and the carbon atoms towhich they are attached to form a substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl orsubstituted or unsubstituted heterocyclyl moiety; and Q is a substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkenyl or substituted or a unsubstituted heterocyclyl,unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy or acylamino.

The invention further embraces compounds of the formula (A-1):

or a salt or solvate thereof,

wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy;

each R^(2a), R^(2b), R^(3a) and R^(3b) is independently H, hydroxyl,nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is takentogether with the carbon to which it is attached and a geminal R² or R³to form a cycloalkyl moiety or a carbonyl moiety;

each R^(10a), R^(10b), R^(11a) and R^(11b) is independently H, hydroxyl,nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together withthe carbon to which it is attached and a geminal R¹⁰ or R¹¹ to form acycloalkyl moiety or a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each m and q is independently 0 or 1;

each R^(8a), R^(8b), R^(8C) and R^(8d) is independently H, hydroxyl,alkoxy, halo, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₃-C₆ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, or istaken together with a geminal R⁸ to form a moiety of the formula—OCH₂CH₂O—, is taken together with the carbon to which it is attachedand a geminal R⁸ to form a cycloalkyl moiety or a carbonyl moiety, istaken together with a geminal R⁸ to form a methylene or a substitutedmethylene;

R^(8g) is H, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈perhaloalkyl or is taken together with R^(8h) and the carbon atoms towhich they are attached to form a substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl orsubstituted or unsubstituted heterocyclyl moiety and the

bond indicates the presence of either an E or Z double bondconfiguration;

R^(8b) is H, halo, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, C₃-C₈ cycloalkyl, C₁-C₈perhaloalkyl or is taken together with R^(8g) and the carbon atoms towhich they are attached to form a substituted or unsubstituted C₃-C₈cycloalkenyl or substituted or unsubstituted heterocyclyl moiety; and

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano oralkynyl.

In one variation, the compound of the formula (A-1) is provided, whereeach X⁷, X⁸, X⁹, X¹⁰, R¹, R^(10a), R^(10b), R^(11a), R^(11b), q and mare as defined for formula (A-1); each R^(2a), R^(2b), R^(3a) and R^(3b)is independently H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy, or is taken together with the carbon to which itis attached and a geminal R² or R³ to form a carbonyl moiety; eachR^(8a), R^(8b), R^(8c) and R^(8d) is independently H, hydroxyl, C₁-C₈alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy, is taken togetherwith the carbon to which it is attached and a geminal R⁸ to form acycloalkyl moiety or a carbonyl moiety, is taken together with a geminalR⁸ to form a methylene or a substituted methylene; R^(8g) is H,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ perhaloalkyl or istaken together with R^(8h) and the carbon atoms to which they areattached to form a substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl or substituted orunsubstituted heterocyclyl moiety and the

bond indicates the presence of either an E or Z double bondconfiguration; R^(8h) is H, halo, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, unsubstituted C₁-C₈ alkyl,C₁-C₈ alkyl substituted with a carbonylalkoxy, carboxyl or acylaminomoiety, C₂-C₈ alkenyl, C₃-C₈ cycloalkyl, C₁-C₈ perhaloalkyl or is takentogether with R^(8g) and the carbon atoms to which they are attached toform a substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₃-C₈ cycloalkenyl or substituted or unsubstitutedheterocyclyl moiety; and Q is a substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkenyl or substituted ora unsubstituted heterocyclyl, unsubstituted amino, substituted amino,alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy oracylamino.

The substituent groups R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(8a),R^(8b), R^(8c), R^(8d), R^(8g), R^(8h), R^(10a), R^(10b), R^(11a),R^(11b), m, q, Q, X⁷, X⁸, X⁹, and X¹⁰ described herein as suitable forcompounds of formula (A) are also suitable for compounds of formulae(A-1). Variations of formula (A) detailed throughout, where applicable,apply to formula (A-1) the same as if each and every variation werespecifically and individually listed for formula (A-1).

The invention also embraces compounds of the formula (B):

or a salt or solvate thereof;

wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy;

each R^(2a), R^(2b), R^(3a) and R^(3b) is independently H, hydroxyl,nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is takentogether with the carbon to which it is attached and a geminal R² or R³to form a cycloalkyl moiety or a carbonyl moiety;

R^(10a), R^(10b), R^(11a) and R^(11b) is independently H, hydroxyl,nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together withthe carbon to which it is attached and a geminal R¹⁰ or R¹¹ to form acycloalkyl moiety or a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each m and q is independently 0 or 1;

each R^(8a), R^(8b), R^(8c) and R^(8d) is independently H, hydroxyl,alkoxy, halo, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxy,carbonylalkoxy, or is taken together with a geminal R⁸ to form a moietyof the formula —OCH₂CH₂O—, or is taken together with the carbon to whichit is attached and a geminal R⁸ to form a cycloalkyl moiety or acarbonyl moiety;

each R^(ga) and R^(ha) is independently H, hydroxyl, alkoxy, halo,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈alkenyl, C₁-C₈ perhaloalkyl, carboxy, or carbonylalkoxy; or R^(ga) andR^(ha) may be taken together to represent a bond;

R^(gb) and R^(hb) are taken together with the carbon atoms to which theyare attached to form a substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl or substituted orunsubstituted heterocyclyl moiety; and

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano oralkynyl.

In one variation, the compound of the formula (B) is provided, whereeach X⁷, X⁸, X⁹, X¹⁰, R¹, R^(10a), R^(10b), R^(11a), R^(11b), q and mare as defined for formula (B); each R^(2a), R^(2b), R^(3a) and R^(3b)is independently H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy, or is taken together with the carbon to which itis attached and a geminal R² or R³ to form a carbonyl moiety; eachR^(8a), R^(8b), R^(8c) and R^(8d) is independently H, hydroxyl, C₁-C₈alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy, is taken togetherwith the carbon to which it is attached and a geminal R⁸ to form acycloalkyl moiety or a carbonyl moiety, is taken together with a geminalR⁸ to form a methylene or a substituted methylene; each of R^(ga) andR^(ha) is independently H, hydroxyl, or C₁-C₈ alkyl; or R^(ga) andR^(ha) may be taken together to represent a bond; R^(gb) and R^(hb) aretaken together with the carbon atoms to which they are attached to forma substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₃-C₈ cycloalkenyl or substituted or unsubstitutedheterocyclyl moiety; and Q is a substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkenyl or substituted ora unsubstituted heterocyclyl, unsubstituted amino, substituted amino,alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy oracylamino.

The invention also embraces compounds of the formula (Ia):

where:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy;

each R^(2a), R^(2b), R^(3a) and R^(3b) is independently H, hydroxyl,nitro, cyano, halo, substituted or i unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is takentogether with the carbon to which it is attached and a geminal R² or R³to form a cycloalkyl moiety or a carbonyl moiety;

each R^(10a), R^(10b), R^(11a) and R^(11b) is independently H, hydroxyl,nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together withthe carbon to which it is attached and a geminal R¹⁰ or R¹¹ to form acycloalkyl moiety or a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8e) and R^(8f) is independently H, hydroxyl, alkoxy, halo,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈alkenyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy, or R^(8e) andR^(8f) are taken together to form a moiety of the formula —OCH₂CH₂O—, amethylene or a substituted methylene, or R^(8e) and R^(8f) are takentogether with the carbon to which they are attached to form a cycloalkylmoiety or a carbonyl moiety;

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano oralkynyl;

or a salt or solvate thereof.

In one variation, the compound of the formula (Ia) is provided, whereeach X⁷, X⁸, X⁹, X¹⁰, R¹, R^(10a), R^(10b), R^(11a), R^(11b), q and mare as defined for formula (Ia); each R^(2a), R^(2b), R^(3a) and R^(3b)is independently H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy, or is taken together with the carbon to which itis attached and a geminal R² or R³ to form a carbonyl moiety; eachR^(8e) and R^(8f) is independently H, hydroxyl, C₁-C₈ alkyl, C₁-C₈perhaloalkyl, carboxy, carbonylalkoxy, is taken together with the carbonto which it is attached and a geminal R⁸ to form a cycloalkyl moiety ora carbonyl moiety or is taken together with a geminal R⁸ to form amethylene or a substituted methylene; and Q is a substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylor substituted or a unsubstituted heterocyclyl, unsubstituted amino,substituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy,aminocarbonylalkoxy or acylamino; or a salt or solvate thereof.

In one variation, the compound of the invention is of the formula (Ia),where each R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b), R^(11a) andR^(11b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, hydroxyl, alkoxy, cyano, nitro or is taken together with thecarbon to which it is attached to and a geminal R group to form acarbonyl moiety or a cycloalkyl moiety. In another variation, thecompound is of the formula (I), where each R^(2a), R^(2b), R^(3a) andR^(3b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, hydroxyl, alkoxy, cyano, nitro or is taken together with thecarbon to which it is attached to and a geminal R group to form acarbonyl moiety and each R^(10a), R^(10b), R^(11a) and R^(11b) isindependently H, substituted or unsubstituted C₁-C₈ alkyl or is takentogether with the carbon to which it is attached to and a geminal Rgroup to form a carbonyl moiety or a cycloalkyl moiety (e.g.cyclopropyl). In another variation, the compound is of the formula (Ia),where Q is a substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl or substituted or aunsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy,aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino.

The invention also embraces compounds of the formula (Ib):

where:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy;

each R^(2a), R^(2b), R^(3a) and R^(3b) is independently H, hydroxyl,nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is takentogether with the carbon to which it is attached and a geminal R² or R³to form a cycloalkyl moiety or a carbonyl moiety;

each R^(10a), R^(10b), R^(11a) and R^(11b) is independently H, hydroxyl,nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together withthe carbon to which it is attached and a geminal R¹⁰ or R¹¹ to form acycloalkyl moiety or a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy, alkoxy, halo,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₂-C₈alkenyl, or is taken together with a geminal R⁸ to form a moiety of theformula —OCH₂CH₂O—, is taken together with the carbon to which it isattached and a geminal R⁸ to form a cycloalkyl moiety or a carbonylmoiety, is taken together with a geminal R⁸ to form a methylene or asubstituted methylene, is taken together with a vicinal R⁸ and thecarbon atoms to which they are attached to form a substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or istaken together with a vicinal R⁸ to form a bond, provided when an R⁸ istaken together with a vicinal R⁸ to form a bond, the geminal R⁸ is otherthan hydroxyl;

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano oralkynyl;

or a salt or solvate thereof.

In one variation, the compound of the formula (Ib) is provided, whereeach X⁷, X⁸, X⁹, X¹⁰, R¹, R^(10a), R^(10b), R^(11a), R^(11b), q and mare as defined for formula (Ib); each R^(2a), R^(2b), R^(3a) and R^(3b)is independently H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy, or is taken together with the carbon to which itis attached and a geminal R² or R³ to form a carbonyl moiety; eachR^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independently H,hydroxyl, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy, istaken together with the carbon to which it is attached and a geminal R⁸to form a cycloalkyl moiety or a carbonyl moiety, is taken together witha geminal R⁸ to form a methylene or a substituted methylene, is takentogether with a vicinal R⁸ and the carbon atoms to which they areattached to form a substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl or substituted orunsubstituted heterocyclyl moiety or is taken together with a vicinal R⁸to form a bond, provided: (i) at most one pair of vicinal R⁸ groups aretaken together to form a bond; and (ii) when an R⁸ is taken togetherwith a vicinal R⁸ to form a bond, the geminal R⁸ is other than hydroxyl;and Q is a substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl or substituted or aunsubstituted heterocyclyl, unsubstituted amino, substituted amino,alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy oracylamino; or a salt or solvate thereof.

In one variation, the compound of the invention is of the formula (Ib),where each R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b), R^(11a) andR^(11b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, hydroxyl, alkoxy, cyano, nitro or is taken together with thecarbon to which it is attached to and a geminal R group to form acarbonyl moiety or a cycloalkyl moiety. In another variation, thecompound is of the formula (I), where each R^(2a), R^(2b), R^(3a) andR^(3b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, hydroxyl, alkoxy, cyano, nitro or is taken together with thecarbon to which it is attached to and a geminal R group to form acarbonyl moiety and each R^(10a), R^(10b), R^(11a) and R^(11b) isindependently H, substituted or unsubstituted C₁-C₈ alkyl or is takentogether with the carbon to which it is attached to and a geminal Rgroup to form a carbonyl moiety or a cycloalkyl moiety (e.g.cyclopropyl). In another variation, the compound is of the formula (Ib),where Q is a substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl or substituted or aunsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy,aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino.

The invention also embraces compound of the formula (Ic):

where:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy;

each R^(2a), R^(2b), R^(3a) and R^(3b) is independently H, hydroxyl,nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is takentogether with the carbon to which it is attached and a geminal R² or R³to form a cycloalkyl moiety or a carbonyl moiety;

each R^(10a), R^(10b), R^(11a) and R^(11b) is independently H, hydroxyl,nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together withthe carbon to which it is attached and a geminal R¹⁰ or R¹¹ to form acycloalkyl moiety or a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8c), R^(8d), R^(8e) and R^(8f) is independently H, hydroxyl,C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy, alkoxy, halo, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₃-C₆ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, or istaken together with a geminal R⁸ to form a moiety of the formula—OCH₂CH₂O—, is taken together with the carbon to which it is attachedand a geminal R⁸ to form a cycloalkyl moiety or a carbonyl moiety, istaken together with a geminal R⁸ to form a methylene or a substitutedmethylene, is taken together with a vicinal R⁸ and the carbon atoms towhich they are attached to form a substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl orsubstituted or unsubstituted heterocyclyl moiety or is taken togetherwith a vicinal R⁸ to form a bond, provided when an R⁸ is taken togetherwith a vicinal R⁸ to form a bond, the geminal R⁸ is other than hydroxyl;

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano oralkynyl;

or a salt or solvate thereof.

In one variation, the compound of the formula (Ic) is provided, whereeach X⁷, X⁸, X⁹, X¹⁰, R¹, R^(10a), R^(10b), R^(11a), R^(11b), and m areas defined for formula (Ic); each R^(2a), R^(2b), R^(3a) and R^(3b) isindependently H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy, or is taken together with the carbon to which itis attached and a geminal R² or R³ to form a carbonyl moiety; eachR^(8c), R^(8d), R^(8e) and R^(8f) is independently H, hydroxyl, C₁-C₈alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy, is taken togetherwith the carbon to which it is attached and a geminal R⁸ to form acycloalkyl moiety or a carbonyl moiety, is taken together with a geminalR⁸ to form a methylene or a substituted methylene, is taken togetherwith a vicinal R⁸ and the carbon atoms to which they are attached toform a substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₃-C₈ cycloalkenyl or substituted or unsubstitutedheterocyclyl moiety or is taken together with a vicinal R⁸ to form abond, provided: (i) at most one pair of vicinal R⁸ groups are takentogether to form a bond; and (ii) when an R⁸ is taken together with avicinal R⁸ to form a bond, the geminal R⁸ is other than hydroxyl; and Qis a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl or substituted or a unsubstitutedheterocyclyl, unsubstituted amino, substituted amino, alkoxy, aminoacyl,acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino; or a salt orsolvate thereof.

In one variation, the compound of the invention is of the formula (Ic),where each R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b), R^(11a) andR^(11b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, hydroxyl, alkoxy, cyano, nitro or is taken together with thecarbon to which it is attached to and a geminal R group to form acarbonyl moiety or a cycloalkyl moiety. In another variation, thecompound is of the formula (I), where each R^(2a), R^(2b), R^(3a) andR^(3b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, hydroxyl, alkoxy, cyano, nitro or is taken together with thecarbon to which it is attached to and a geminal R group to form acarbonyl moiety and each R^(10a), R^(10b), R^(11a) and R^(11b) isindependently H, substituted or unsubstituted C₁-C₈ alkyl or is takentogether with the carbon to which it is attached to and a geminal Rgroup to form a carbonyl moiety or a cycloalkyl moiety (e.g.cyclopropyl). In another variation, the compound is of the formula (Ic),where Q is a substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl or substituted or aunsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy,aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino. Inanother variation, the compound is of the formula (Ic), provided thatwhen R^(8c) and R^(8d) are hydrogen and R^(8e) and R^(8f) are takentogether with the carbon to which they are attached to form a carbonylmoiety, then Q is other than —NHR where R is selected from substitutedor unsubstituted aryl and substituted or unsubstituted heteroaryl.

In one embodiment, the compound is of the formula (Ic) where R^(8c) andR^(8e) are taken together to form a bond, each R^(8d) and R^(8f) isindependently H, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy,carbonylalkoxy, or R^(8d) and R^(8f) are taken together with the carbonatoms to which they are attached to form a substituted or unsubstitutedC₃-C₈ cycloalkenyl or substituted or unsubstituted heterocyclyl moiety.In one embodiment, the compound is of the formula (C) and the

bond indicates the presence of either an E or Z double bondconfiguration:

In one variation, the compound is of the formula (C), wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy;

each R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b), R^(11a) andR^(11b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, hydroxyl, alkoxy, cyano, nitro or is taken together with thecarbon to which it is attached to and a geminal R group to form acarbonyl moiety or a cycloalkyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

R^(8d) is H, C₁-C₈ perhaloalkyl, alkoxy, halo, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, or is takentogether with R^(8f) and the carbon atoms to which they are attached toform a substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₃-C₈ cycloalkenyl or substituted or unsubstitutedheterocyclyl moiety and the

bond indicates the presence of either an E or Z double bondconfiguration;

R^(8f) is H, C₁-C₈ perhaloalkyl, alkoxy, halo, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, or is takentogether with R^(8d) and the carbon atoms to which they are attached toform a substituted or unsubstituted C₃-C₈ cycloalkenyl or substituted orunsubstituted heterocyclyl moiety;

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano oralkynyl;

or a salt or solvate thereof.

In one variation, the compound of the formula (C) is provided, whereeach X⁷, X⁸, X⁹, X¹⁰, R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a),R^(10b), R^(11a), R^(11b), q and m are as defined for formula (C);R^(8d) is H, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ perhaloalkyl or istaken together with R^(8f) and the carbon atoms to which they areattached to form a substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl or substituted orunsubstituted heterocyclyl moiety and the

bond indicates the presence of either an E or Z double bondconfiguration; R^(8f) is H, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈perhaloalkyl or is taken together with R^(8d) and the carbon atoms towhich they are attached to form a substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl orsubstituted or unsubstituted heterocyclyl moiety; and Q is a substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkenyl or substituted or a unsubstituted heterocyclyl,unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy or acylamino; or a salt or solvatethereof.

In one variation, the compound is of the formula (C), wherein at leastone of the X⁷, X⁸, X⁹ and X¹⁰ is CR⁴, where each R⁴ is independently H,hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,C₁-C₈ alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl. In anothervariation, each X⁷, X⁸, X⁹ and X¹⁰ is CR⁴. In another variation, one ofX⁷, X⁸, X⁹ and X¹⁰ is CR⁴ and the others are CH. In another variation,two of X⁷, X⁸, X⁹ and X¹⁰ are CR⁴ and the others are CH. In onevariation, at least one of X⁷, X⁸, X⁹ and X¹⁰ is CR⁴ where R⁴ is halo,C₁-C₈ perhaloalkyl or substituted or unsubstituted C₁-C₈ alkyl. Inanother variation, each X⁷, X⁸ and X¹⁰ is CH and X⁹ is CR⁴ where R⁴ ishalo, C₁-C₈ perhaloalkyl or substituted or unsubstituted C₁-C₈ alkyl. Inanother variation, each X⁷, X⁸ and X¹⁰ is CH and X⁹ is CR⁴ where R⁴ ishalo, e.g. chloro or fluoro. In another variation, each X⁷, X⁸ and X¹⁰is CH and X⁹ is CR⁴ where R⁴ is unsubstituted C₁-C₈ alkyl, e.g. methyl.In another variation, each X⁷, X⁸ and X¹⁰ is CH and X⁹ is CR⁴ where R⁴is unsubstituted C₁-C₈ perhaloalkyl, e.g. CF₃. In one variation, thecompound is of the formula (C), where Q is substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl orsubstituted or a unsubstituted heterocyclyl. In another variation, Q issubstituted or unsubstituted heteroaryl, e.g. substituted orunsubstituted pyridyl. In another variation, Q is substituted orunsubstituted aryl, e.g. substituted or unsubstituted phenyl. In anothervariation, Q is phenyl substituted with one or more of the substituentsselected from halo, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl and alkoxy, e.g.4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl,4-(trifluoromethyl)phenyl, 3,4-difluorophenyl, 3-chloro-4-fluorophenyl,4-methoxyl-2-fluorophenyl, 4-methoxyl-3-fluorophenyl and3-methoxy-4-fluorophenyl. In one variation, the compound is of theformula (C), where each R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a),R^(10b), R^(11a) and R^(11b) is independently H, substituted orunsubstituted C₁-C₈ alkyl. In another variation, R¹ is substituted orunsubstituted C₁-C₈ alkyl, e.g. methyl. In another variation, eachR^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b), R^(11a) and R^(11b) isH. In another variation, R¹ is substituted or unsubstituted C₁-C₈ alkyl,e.g. methyl, and each R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b),R^(11a) and R^(11b) is H. In one variation, the compound is of theformula (C), where each R^(8d) and R^(8f) is independently H, C₁-C₈perhaloalkyl or substituted or unsubstituted C₁-C₈ alkyl. In anothervariation, each R^(8d) and R^(8f) is independently H or unsubstitutedC₁-C₈ alkyl, e.g. methyl, ethyl and cyclopropyl. In another variation,the compound is of the formula (C) where each X⁷, X⁸ and X¹⁰ is CH andX⁹ is CR⁴ where R⁴ is halo, C₁-C₈ perhaloalkyl or substituted orunsubstituted C₁-C₈ alkyl (e.g. methyl), R¹ is substituted orunsubstituted C₁-C₈ alkyl (e.g. methyl), each R^(2a), R^(2b), R^(3a),R^(3b), R^(10a), R^(10b), R^(11a) and R^(11b) is H, each R^(8d) andR^(8f) is independently H or unsubstituted C₁-C₈ alkyl, and Q issubstituted or unsubstituted aryl, e.g. substituted or unsubstitutedphenyl.

In one variation, compounds of the formula (X-1) are provided:

or a salt or solvate thereof, where R¹, R⁴, R^(8f) and Q are defined asfor formula (C) and, where applicable, any variation thereof detailedherein. That is, variations of formula (C) detailed throughout, whereapplicable, apply to formula (X-1) the same as if each and everyvariation were specifically and individually listed for formula (X-1).

In one variation, compounds of the formula (X-1) are provided, or a saltor solvate thereof, where R¹ is a substituted or unsubstituted C₁-C₈alkyl; R⁴ is H, halo, trifluoromethyl, a C₁-C₈ unsubstituted alkyl or asubstituted amino; R^(8f) is substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted aryl, halo and alkoxy; Q is substitutedaryl or a substituted or unsubstituted heteroaryl and the

bond indicates the presence of either an E or Z double bondconfiguration. In one variation of formula (X-1), R¹ is an unsubstitutedC₁₋₈ alkyl or a C₁-C₈ alkyl substituted with a halo or hydroxyl group.In one such variation, R¹ is methyl, 2-haloethyl (e.g., 2-fluoroethyl),2,2,2-trifluoroethyl, or a hydroxyl-substituted pentyl group. In aparticular variation of formula (X-1), R¹ is —CH₃, —CH₂CH₂F, —CH₂CF₃, or—CH₂CH₂C(CH₃)₂OH. In another variation of formula (X-1), R⁴ is H, halo,methyl, trifluoromethyl, or a substituted amino of the formula—N(H)(C₁-C₈unsubstituted alkyl). When R⁴ is a halo (e.g., fluoro orchloro), in one aspect R⁴ is chloro. In one variation of formula (X-1),R⁴ is H, methyl or chloro. In one variation of formula (X-1), R⁴ ismethyl or chloro. When R⁴ is a substituted amino of the formula—N(H)(C₁-C₈unsubstituted alkyl), in one aspect C₁-C₈unsubstituted alkylis a linear C₁-C₈unsubstituted alkyl such as methyl or ethyl. In aparticular variation of formula (X-1), R⁴ is —N(H)(CH₃). It isunderstood that any R¹ for formula (X-1) may be combined with any R⁴ offormula (X-1) the same as if each and every combination wherespecifically and individually listed. For example, compounds of theformula (X-1) are provided where R¹ is —CH₃, —CH₂CH₂F, —CH₂CF₃, or—CH₂CH₂C(CH₃)₂OH and R⁴ is H, chloro, fluoro, methyl, trifluoromethyl,or —N(H)(CH₃) Likewise, compounds of the formula (X-1) are providedwhere R¹ is methyl and R⁴ is H, halo, methyl or a substituted amino ofthe formula —N(H)(C₁-C₈unsubstituted alkyl). In one such aspect,compounds of the formula (X-1) are provided where R¹ is methyl and R⁴ isH, halo or methyl. In one such aspect, compounds of the formula (X-1)are provided where R¹ is methyl and R⁴ is halo (e.g., fluoro or chloro),trifluoromethyl, or methyl. In one variation of formula (X-1), R^(8f) isan unsubstituted C₁₋₈ alkyl or a C₁-C₈ alkyl substituted with a halo,hydroxyl, carboxyl or acylamino group. In one such variation, R^(8f) ismethyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclohexyl,halo (e.g., fluoro), a carboxyl-substituted methyl group or anamido-substituted methyl group. In a particular variation, R^(8f) ismethyl. When Q of formula (X-1) is a substituted aryl, in one aspect Qis a substituted phenyl. In one aspect, Q is a 0 phenyl. In a particularaspect, Q of formula (X-1) is a halo-substituted phenyl,alkoxy-substituted phenyl or an acylamino-substituted phenyl. Thus,compounds of the formula (X-1) are provided where Q in one variation isa phenyl mono-substituted with a fluoro, C₁-C₈ alkoxy (e.g., methoxy),an acylamino moiety of the formula —C(O)NH(C₁-C₈unsubstituted alkyl) oran acylamino moiety of the formula —C(O)N(C₁-C₈ unsubstituted alkyl)₂,such as 2-fluoro-phenyl, 4-fluoro-phenyl, 4-methoxy-phenyl,4-(C(O)NH(CH₃) and 4-(C(O)N(CH₃)₂)-phenyl. In one aspect, Q is adi-substituted phenyl. In one aspect, Q of formula (X-1) is a di-halosubstituted phenyl group such as 3,4-difluoro-phenyl. In a particularaspect, Q of formula (C-1) is a phenyl group substituted with one halogroup and one C₁-C₈ alkoxy group (e.g., methoxy). Thus, compounds of theformula (X-1) are provided where Q in one variation is a phenylsubstituted with a fluoro and a C₁-C₈ alkoxy group, such as3-fluoro-4-methoxy-phenyl. When Q of formula (X-1) is a substituted orunsubstituted heteroaryl, in one variation the substituted orunsubstituted heteroaryl is a pyridyl or pyrimidyl moiety. Thus, in oneaspect of formula (X-1), Q is an unsubstituted pyridyl or pyrimidyl,such as 3-pyridyl, 4-pyridyl and 4-pyrimidyl. In another aspect offormula (X-1), Q is a substituted pyridyl, such as 6-methyl-3-pyridyl.It is understood that any Q for formula (X-1) may be combined with anyR¹ and/or R⁴ of formula (X-1) the same as if each and every combinationwhere specifically and individually listed. For example, compounds ofthe formula (X-1) are provided where R¹ is —CH₃, —CH₂CH₂F, —CH₂CF₃, or—CH₂CH₂C(CH₃)₂OH; R⁴ is H, chloro, fluoro, methyl, trifluoromethyl, or—N(H)(CH₃) and Q is 4-pyridyl, 3-pyridyl, 6-methyl-3-pyridyl,6-pyrimidyl, 4-fluoro-phenyl, 4-methoxy-phenyl,3-fluoro-4-methoxy-phenyl or 4-dimethylcarbamoyl-phenyl. Likewise,compounds of the formula (X-1) are provided where R¹ is methyl; R⁴ is H,halo or methyl and Q is an unsubstituted pyridyl. In any variation offormula (X-1), in one aspect, the

bond indicates the presence of an E double bond configuration. In anyvariation of formula (X-1), in one aspect, the

bond indicates the presence of a Z double bond configuration.

In specific variations, compounds of the formula (X-1) have the formula:

or a salt or solvate thereof; wherein R¹, R⁴, R^(8f) and Q are definedas for formula (X-1) and, where applicable, any variation thereofdetailed herein. That is, variations of formula (X-1) detailedthroughout, where applicable, apply to formulae (X-1a) and (X-1b) thesame as if each and every variation were specifically and individuallylisted for formulae (X-1a) and (X-1b). In one particular aspect offormula (X-1a), R¹ is —CH₃, —CH₂CH₂F, —CH₂CF₃, or —CH₂CH₂C(CH₃)₂OH; R⁴is H, chloro, fluoro, methyl, trifluoromethyl, or —N(H)(CH₃) R^(8f) isan unsubstituted C₁₋₈ alkyl or a C₁-C₈ alkyl substituted with a halo,hydroxyl, carboxyl or acylamino group. In one such variation, R¹ ismethyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclohexyl,halo (e.g., fluoro), a carboxyl-substituted methyl group or aamido-substituted methyl group and Q is 4-pyridyl, 3-pyridyl,6-methyl-3-pyridyl, 6-pyrimidyl, 4-fluoro-phenyl, 4-methoxy-phenyl,3-fluoro-4-methoxy-phenyl or 4-dimethylcarbamoyl-phenyl. In anotheraspect of formula (X-1a), R¹ is methyl, R⁴ is H, chloro or methyl,R^(8f) is methyl. and Q is a substituted or unsubstituted pyridyl. Inone particular aspect of formula (X-1b), R¹ is methyl, R⁴ is methyl,R^(8f) is methyl. and Q is a substituted or unsubstituted pyridyl.Pharmaceutically acceptable salts of compounds of the formula (X-1),(X-1a) and (X-1b) are also provided.

In one variation, compounds of the formula (X-2) are provided:

or a salt or solvate thereof, where R¹ is a substituted or unsubstitutedC₁-C₈ alkyl; R⁴ is H, halo or a C₁-C₈ unsubstituted alkyl, R^(8f) issubstituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedaryl, halo and alkoxy and the

bond indicates the presence of either an E or Z double bondconfiguration and where R⁴ and the pyridyl moiety may be connected tothe parent structure at any available position. In one variation offormula (X-2), R¹ is an unsubstituted C₁₋₈ alkyl or a C₁-C₈ alkylsubstituted with a halo or hydroxyl group. In one such variation, R¹ ismethyl, 2-haloethyl (e.g., 2-fluoroethyl), 2,2,2-trifluoroethyl, or ahydroxyl-substituted pentyl group. In a particular variation of formula(X-2), R¹ is —CH₃, —CH₂CH₂F, —CH₂CF₃, or —CH₂CH₂C(CH₃)₂OH. In anothervariation of formula (X-2), R⁴ is H, halo, trifluoromethyl, or methyl.When R⁴ is a halo (e.g., fluoro or chloro), in one aspect R⁴ is chloro.In one variation of formula (X-2), R⁴ is H, methyl or chloro. In onevariation of formula (X-2), R⁴ is methyl or chloro. In one variation offormula (X-1), R^(8f) is an unsubstituted C₁₋₈ alkyl or a C₁-C₈ alkylsubstituted with a halo, hydroxyl, carboxyl or acylamino group. In onesuch variation, R¹ is methyl, ethyl, isopropyl, t-butyl, cyclopropyl,cyclobutyl, cyclohexyl, halo (e.g., fluoro), a carboxyl-substitutedmethyl group or an amido-substituted methyl group. In a particularvariation, R^(8f) is methyl. It is understood that any R¹ for formula(X-2) may be combined with any R⁴ of formula (X-2) the same as if eachand every combination were specifically and individually listed. Forexample, compounds of the formula (X-2) are provided where R¹ is —CH₃,—CH₂CH₂F, —CH₂CF₃, or —CH₂CH₂C(CH₃)₂OH and R⁴ is H, chloro, fluoro,trifluoromethyl, or methyl Likewise, compounds of the formula (X-2) areprovided where R¹ is methyl and R⁴ is H, halo or methyl. In one suchaspect, compounds of the formula (X-2) are provided where R¹ is methyland R⁴ is halo (e.g., fluoro or chloro), trifluoromethyl, or methyl. Inany variation of formula (X-2), in one aspect, the

bond indicates the presence of an E double bond configuration. In anyvariation of formula (X-2), in one aspect, the

bond indicates the presence of a Z double bond configuration.

In specific variations, compounds of the formula (X-2) have the formula:

or a salt or solvate thereof; wherein R¹, R⁴ and R^(8f) are defined asfor formula (X-2). That is, variations of formula (X-2) detailedthroughout, where applicable, apply to formulae (X-2a) and (X-2b) thesame as if each and every variation were specifically and individuallylisted for formulae (X-2a) and (X-2b). Pharmaceutically acceptable saltsof compounds of the formula (X-2), (X-2a) and (X-2b) are also provided.

Compounds of the formula (X-3) and (X-4) are also provided:

or a salt or solvate thereof, wherein R¹ is CH₃, —CH₂CH₂—C(CH₃)₂(OH),—CH₂CF₃, or —CH₂CH₂F; R^(4a) is H or F; R^(4c) is H, CH₃, Cl, F, CF₃, or—NHCH₃; R^(9b) is H or F; R⁹ is F, OCH₃, —CONH(CH₃) or —CON(CH₃)₂ andR^(8f) is an unsubstituted C₁₋₈ alkyl or a C₁-C₈ alkyl substituted witha halo, hydroxyl, carboxyl or acylamino group. In one embodiment offormula (X-3) and (X-4), R¹ is CH₃; R^(4a) is H; R^(4c) is CH₃, Cl, F or—NHCH₃; R^(9b) is H or F; R⁹ is F, OCH₃, —CONH(CH₃) or —CON(CH₃)₂; andR^(8f) is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl,cyclohexyl, halo (e.g., fluoro), a carboxyl-substituted methyl group ora amido-substituted methyl group. In a further embodiment, R¹ is CH₃;R^(4a) is H; R^(4c) is CH₃, Cl, F or —NHCH₃; R^(9b) is H; R^(9c) is F,OCH₃; and R^(8f) is methyl

Compounds of the formula (X-5) and (X-6) are also embraced,

or a salt or solvate thereof, wherein R¹ is CH₃, —CH₂CH₂—C(CH₃)₂(OH),—CH₂CF₃, or —CH₂CH₂F; R^(4a) is H or F; R^(4c) is H, CH₃, Cl, F, CF₃, or—NHCH₃; and R^(8f) is methyl, ethyl, isopropyl, t-butyl, cyclopropyl,cyclobutyl, cyclohexyl, halo (e.g., fluoro), a carboxyl-substitutedmethyl group or a amido-substituted methyl group. In one embodiment offormula (X-5) and (X-6) R¹ is CH₃; R^(4a) is H; R^(4c) is CH₃, Cl, F or—NHCH₃; and R^(8f) is CH₃. In yet another variation, R¹ is CH₃; R^(4a)is H; R^(4c) is CH₃, Cl or F; and R^(8f) is CH₃.

In one variation, compounds of the formula (X-7) or (X-8) are provided

or a salt or solvate thereof, wherein R¹ is CH₃, —CH₂CH₂—C(CH₃)₂(OH),—CH₂CF₃, or —CH₂CH₂F; R^(4a) is H or F; R^(4c) is H, CH₃, Cl, F, CF₃, or—NHCH₃; R^(9c) is H, F, CH₃, CF₃, OCH₃, —CONH(CH₃) or —CON(CH₃)₂; andR^(8f) is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl,cyclohexyl, halo (e.g., fluoro), a carboxyl-substituted methyl group ora amido-substituted methyl group. In one variation of formula (X-7) and(X-8) R¹ is CH₃; R^(4a) is H; R^(4c) is CH₃, Cl, F, CF₃, or —NHCH₃; andR^(9c) is H, F, CF₃, or CH₃; and R^(8f) is methyl. In a particularvariation, R¹ is CH₃; R^(4a) is H; R^(4c) is CH₃, CF₃, Cl or F; andR^(9c) is H, CF₃, or CH₃.

In another variation, compounds of the formula (X-9) and (X-10) areprovided:

or a salt or solvate thereof, wherein R¹ is CH₃, —CH₂CH₂—C(CH₃)₂(OH),—CH₂CF₃, or —CH₂CH₂F; R^(4a) is H or F; and R^(4c) is H, CH₃, Cl, F,—CF₃, or —NHCH₃. R^(8f) is methyl, ethyl, isopropyl, t-butyl,cyclopropyl, cyclobutyl, cyclohexyl, halo (e.g., fluoro), acarboxyl-substituted methyl group or a amido-substituted methyl group Inone embodiment of formula (X-9) and (X-10), R¹ is CH₃; R^(4a) is H; andR^(4c) is CH₃, Cl, F, CF₃, or —NHCH₃. In one embodiment R¹ is CH₃;R^(4a) is H; R^(4c) is CH₃, CF₃, Cl or F; and R^(8f) is methyl.

In one variation, compounds of the formula (C-1) are provided:

or a salt or solvate thereof, where R¹, R⁴ and Q are defined as forformula (C) and, where applicable, any variation thereof detailedherein. That is, variations of formula (C) detailed throughout, whereapplicable, apply to formula (C-1) the same as if each and everyvariation were specifically and individually listed for formula (C-1).

In one variation, compounds of the formula (C-1) are provided, or a saltor solvate thereof, where R¹ is a substituted or unsubstituted C₁-C₈alkyl; R⁴ is H, halo, trifluoromethyl, a C₁-C₈ unsubstituted alkyl or asubstituted amino; Q is substituted aryl or a substituted orunsubstituted heteroaryl and the

bond indicates the presence of either an E or Z double bondconfiguration. In one variation of formula (C-1), R¹ is an unsubstitutedC₁₋₈ alkyl or a C₁-C₈ alkyl substituted with a halo or hydroxyl group.In one such variation, R¹ is methyl, 2-haloethyl (e.g., 2-fluoroethyl),2,2,2-trifluoroethyl, or a hydroxyl-substituted pentyl group. In aparticular variation of formula (C-1), R¹ is —CH₃, —CH₂CH₂F, —CH₂CF₃, or—CH₂CH₂C(CH₃)₂OH. In another variation of formula (C-1), R⁴ is H, halo,methyl, trifluoromethyl, or a substituted amino of the formula—N(H)(C₁-C₈unsubstituted alkyl). When R⁴ is a halo (e.g., fluoro orchloro), in one aspect R⁴ is chloro. In one variation of formula (C-1),R⁴ is H, methyl or chloro. In one variation of formula (C-1), R⁴ ismethyl or chloro. When R⁴ is a substituted amino of the formula—N(H)(C₁-C₈unsubstituted alkyl), in one aspect C₁-C₈unsubstituted alkylis a linear C₁-C₈unsubstituted alkyl such as methyl or ethyl. In aparticular variation of formula (C-1), R⁴ is —N(H)(CH₃). It isunderstood that any R¹ for formula (C-1) may be combined with any R⁴ offormula (C-1) the same as if each and every combination wherespecifically and individually listed. For example, compounds of theformula (C-1) are provided where R¹ is —CH₃, —CH₂CH₂F, —CH₂CF₃, or—CH₂CH₂C(CH₃)₂OH and R⁴ is H, chloro, fluoro, methyl, trifluoromethyl,or —N(H)(CH₃). Likewise, compounds of the formula (C-1) are providedwhere R¹ is methyl and R⁴ is H, halo, methyl or a substituted amino ofthe formula —N(H)(C₁-C₈unsubstituted alkyl). In one such aspect,compounds of the formula (C-1) are provided where R¹ is methyl and R⁴ isH, halo, trifluoromethyl, or methyl. In one such aspect, compounds ofthe formula (C-1) are provided where R¹ is methyl and R⁴ is halo (e.g.,fluoro or chloro) or methyl. When Q of formula (C-1) is a substitutedaryl, in one aspect Q is a substituted phenyl. In one aspect, Q is amono-substituted phenyl. In a particular aspect, Q of formula (C-1) is ahalo-substituted phenyl, alkoxy-substituted phenyl or aacylamino-substituted phenyl. Thus, compounds of the formula (C-1) areprovided where Q in one variation is a phenyl mono-substituted with afluoro, C₁-C₈ alkoxy (e.g., methoxy), an acylamino moiety of the formula—C(O)NH(C₁-C₈ unsubstituted alkyl) or an acylamino moiety of the formula—C(O)N(C₁-C₈ unsubstituted alkyl)₂, such as 2-fluoro-phenyl,4-fluoro-phenyl, 4-methoxy-phenyl, 4-(C(O)NH(CH₃) and4-(C(O)N(CH₃)₂)-phenyl. In one aspect, Q is a di-substituted phenyl. Inone aspect, Q of formula (C-1) is a di-halo substituted phenyl groupsuch as 3,4-difluoro-phenyl. In a particular aspect, Q of formula (C-1)is a phenyl group substituted with one halo group and one C₁-C₈ alkoxygroup (e.g., methoxy). Thus, compounds of the formula (C-1) are providedwhere Q in one variation is a phenyl substituted with a fluoro and aC₁-C₈ alkoxy group, such as 3-fluoro-4-methoxy-phenyl. When Q of formula(C-1) is a substituted or unsubstituted heteroaryl, in one variation thesubstituted or unsubstituted heteroaryl is a pyridyl or pyrimidylmoiety. Thus, in one aspect of formula (C-1), Q is an unsubstitutedpyridyl or pyrimidyl, such as 3-pyridyl, 4-pyridyl and 4-pyrimidyl. Inanother aspect of formula (C-1), Q is a substituted pyridyl, such as6-methyl-3-pyridyl. It is understood that any Q for formula (C-1) may becombined with any R¹ and/or R⁴ of formula (C-1) the same as if each andevery combination where specifically and individually listed. Forexample, compounds of the formula (C-1) are provided where R¹ is —CH₃,—CH₂CH₂F, —CH₂CF₃, or —CH₂CH₂C(CH₃)₂OH; R⁴ is H, chloro, fluoro,trifluoromethyl, methyl or —N(H)(CH₃) and Q is 4-pyridyl, 3-pyridyl,6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, 6-pyrimidyl,4-fluoro-phenyl, 4-methoxy-phenyl, 3-fluoro-4-methoxy-phenyl or4-dimethylcarbamoyl-phenyl. Likewise, compounds of the formula (C-1) areprovided where R¹ is methyl; R⁴ is H, halo or methyl and Q is anunsubstituted pyridyl. In any variation of formula (C-1), in one aspect,the

bond indicates the presence of an E double bond configuration. In anyvariation of formula (C-1), in one aspect, the

bond indicates the presence of a Z double bond configuration.

In specific variations, compounds of the formula (C-1) have the formula:

or a salt or solvate thereof; wherein R¹, R⁴ and Q are defined as forformula (C-1) and, where applicable, any variation thereof detailedherein. That is, variations of formula (C-1) detailed throughout, whereapplicable, apply to formulae (C-1a) and (C-1b) the same as if each andevery variation were specifically and individually listed for formulae(C-1a) and (C-1b). In one particular aspect of formula (C-1a), R¹ is—CH₃, —CH₂CH₂F, —CH₂CF₃, or —CH₂CH₂C(CH₃)₂OH; R⁴ is H, chloro, fluoro,methyl trifluoromethyl, or —N(H)(CH₃) and Q is 4-pyridyl, 3-pyridyl,6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, 6-pyrimidyl,4-fluoro-phenyl, 4-methoxy-phenyl, 3-fluoro-4-methoxy-phenyl or4-dimethylcarbamoyl-phenyl. In another aspect of formula (C-1a), R¹ ismethyl, R⁴ is H, chloro or methyl and Q is a substituted orunsubstituted pyridyl. In one particular aspect of formula (C-1b), R¹ ismethyl, R⁴ is methyl and Q is a substituted or unsubstituted pyridyl.Pharmaceutically acceptable salts of compounds of the formula (C-1),(C-1a) and (C-1b) are also provided.

In one variation, compounds of the formula (C-2) are provided:

or a salt or solvate thereof, where R¹ is a substituted or unsubstitutedC₁-C₈ alkyl; R⁴ is H, halo or a C₁-C₈ unsubstituted alkyl and the

bond indicates the presence of either an E or Z double bondconfiguration and where R⁴ and the pyridyl moiety may be connected tothe parent structure at any available position. In one variation offormula (C-2), R¹ is an unsubstituted C₁₋₈ alkyl or a C₁-C₈ alkylsubstituted with a halo or hydroxyl group. In one such variation, R¹ ismethyl, 2-haloethyl (e.g., 2-fluoroethyl), 2,2,2-trifluoroethyl, or ahydroxyl-substituted pentyl group. In a particular variation of formula(C-2), R¹ is —CH₃, —CH₂CH₂F, —CH₂CF₃, or —CH₂CH₂C(CH₃)₂OH. In anothervariation of formula (C-2), R⁴ is H, halo, trifluoromethyl, or methyl.When R⁴ is a halo (e.g., fluoro or chloro), in one aspect R⁴ is chloro.In one variation of formula (C-2), R⁴ is H, methyl or chloro. In onevariation of formula (C-2), R⁴ is methyl or chloro. It is understoodthat any R¹ for formula (C-2) may be combined with any R⁴ of formula(C-2) the same as if each and every combination were specifically andindividually listed. For example, compounds of the formula (C-2) areprovided where R¹ is —CH₃, —CH₂CH₂F, —CH₂CF₃, or —CH₂CH₂C(CH₃)₂OH and R⁴is H, chloro, fluoro, trifluoromethyl, or methyl. Likewise, compounds ofthe formula (C-2) are provided where R¹ is methyl and R⁴ is H, halo ormethyl. In one such aspect, compounds of the formula (C-2) are providedwhere R¹ is methyl and R⁴ is halo (e.g., fluoro or chloro) or methyl. Inany variation of formula (C-2), in one aspect, the

bond indicates the presence of an E double bond configuration. In anyvariation of formula (C-2), in one aspect, the

bond indicates the presence of a Z double bond configuration.

In specific variations, compounds of the formula (C-2) have the formula:

or a salt or solvate thereof; wherein R¹ and R⁴ are defined as forformula (C-2). That is, variations of formula (C-2) detailed throughout,where applicable, apply to formulae (C-2a) and (C-2b) the same as ifeach and every variation were specifically and individually listed forformulae (C-2a) and (C-2b). Pharmaceutically acceptable salts ofcompounds of the formula (C-2), (C-2a) and (C-2b) are also provided.

Compounds of the formula (C-3a) and (C-3b) are also provided:

or a salt or solvate thereof, wherein R¹ is CH₃, —CH₂CH₂—C(CH₃)₂(OH),—CH₂CF₃, or —CH₂CH₂F; R^(4a) is H or F; R^(4c) is H, CH₃, CF₃, Cl, F or—NHCH₃; R^(9b) is H or F; and R^(9c) is F, OCH₃, —CONH(CH₃) or—CON(CH₃)₂. In one embodiment of formula (C-3a) and (C-3b), R¹ is CH₃;R^(4a) is H; R^(4c) is CH₃, Cl, F, CF₃, or —NHCH₃; R^(9b) is H or F; andR^(9c) is F, OCH₃, —CONH(CH₃) or —CON(CH₃)₂. In a further embodiment, R¹is CH₃; R^(4a) is H; R^(4c) is CH₃, Cl, F or —NHCH₃; R^(9b) is H; andR^(9c) is F, OCH₃.

Compounds of the formula (C-4a) and (C-4b) are also embraced,

or a salt or solvate thereof, wherein R¹ is CH₃, —CH₂CH₂—C(CH₃)₂(OH) or—CH₂CH₂F; R^(4a) is H or F; and R^(4c) is H, CH₃, Cl, F or —NHCH₃. Inone embodiment of formula (C-4a) and (C-4b), R¹ is CH₃; R^(4a) is H andR^(4c) is CH₃, Cl, F, CF₃, or —NHCH₃. In yet another variation, R¹ isCH₃; R^(4a) is H; R^(4c) is CH₃, CF₃, Cl or F.

In one variation, compounds of the formula (C-5a) or (C-5b) are provided

or a salt or solvate thereof, wherein R¹ is CH₃, —CH₂CH₂—C(CH₃)₂(OH),—CH₂CF₃, or —CH₂CH₂F; R^(4a) is H or F; R^(4c) is H, CH₃, Cl, F, CF₃, or—NHCH₃; and R^(9c) is H, F, CH₃, CF₃, OCH₃, —CONH(CH₃) or —CON(CH₃)₂. Inone variation of formula (C-5a) and (C-5b) R¹ is CH₃; R^(4a) is H;R^(4c) is CH₃, Cl, F, CF₃, or —NHCH₃; and R^(9c) is H, F, CF₃, or CH₃.In a particular variation, R¹ is CH₃; R^(4a) is H; R^(4c) is CH₃, Cl orF; and R^(9c) is H, CF₃, or CH₃.

In another variation, compounds of the formula (C-6a) and (C-6b) areprovided:

or a salt or solvate thereof, wherein R¹ is CH₃, —CH₂CH₂—C(CH₃)₂(OH),—CH₂CF₃, or —CH₂CH₂F; R^(4a) is H or F; and R^(4c) is H, CH₃, CF₃, Cl, For —NHCH₃. In one embodiment of formula (C-6a) and (C-6b), R¹ is CH₃;R^(4a) is H; and R^(4c) is CH₃, Cl, F, CF₃, or —NHCH₃. In one embodimentR¹ is CH₃; R^(4a) is H; and R^(4c) is CH₃, CF₃, Cl or F.

In one embodiment, the compound is of the formula (Ic) where R^(8c) andR^(8e) are taken together to form a bond and R^(8d) and R^(8f) are takentogether to form a bond. In one embodiment, the compound is of theformula (D):

In one variation, the compound is of the formula (D), wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy;

each R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b), R^(11a) andR^(11b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, hydroxyl, alkoxy, cyano, nitro or is taken together with thecarbon to which it is attached to and a geminal R group to form acarbonyl moiety or a cycloalkyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano oralkynyl;

or a salt or solvate thereof.

In one variation, compounds of the formula (D-1) are provided:

or a salt or solvate thereof; where R¹, R⁴ and Q are as defined forformula (D). In one variation, Q of formula (D-1) is a substituted orunsubstituted aryl, such as phenyl. In one variation, R⁴ of formula(D-1) is halo, such as chloro. In one aspect, Q of formula (D-1) is amono-substituted phenyl, such as a mono-halo substituted phenyl, forexample 4-fluoro-phenyl. In another aspect, Q of formula (D-1) is adi-substituted phenyl, such as a 3,4-di-substituted phenyl, for example3-fluoro-4-methoxyphenyl. In another variation Q of formula (D-1) is adi-substituted phenyl and R¹ is an unsubstituted C₁-C₈ alkyl such asmethyl. In another variation Q of formula (D-1) is a substituted phenyland R⁴ is halo, such as chloro. In another variation Q of formula (D-1)is a di-substituted phenyl, R⁴ is halo such as chloro and R¹ is anunsubstituted C₁-C₈ alkyl such as methyl.

The invention also embraces compound of the formula (Id):

where:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy;

each R^(2a), R^(2b), R^(3a) and R^(3b) is independently H, hydroxyl,nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is takentogether with the carbon to which it is attached and a geminal R² or R³to form a cycloalkyl moiety or a carbonyl moiety;

each R^(10a), R^(10b), R^(11a) and R^(11b) is independently H, hydroxyl,nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together withthe carbon to which it is attached and a geminal R¹⁰ or R¹¹ to form acycloalkyl moiety or a carbonyl moiety;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each m and q is independently 0 or 1;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy, alkoxy, halo,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₂-C₈alkenyl, or is taken together with a geminal R⁸ to form a moiety of theformula —OCH₂CH₂O—, is taken together with the carbon to which it isattached and a geminal R⁸ to form a cycloalkyl moiety or a carbonylmoiety, is taken together with a geminal R⁸ to form a methylene or asubstituted methylene, is taken together with a vicinal R⁸ and thecarbon atoms to which they are attached to form a substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or istaken together with a vicinal R⁸ to form a bond, provided: (i) at mostone pair of vicinal R⁸ groups are taken together to form a bond; and(ii) when an R⁸ is taken together with a vicinal R⁸ to form a bond, thegeminal R⁸ is other than hydroxyl;

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano oralkynyl;

or a salt or solvate thereof.

In one variation, the compound of the formula (Id) is provided, whereeach R¹, R⁴, R^(10a), R^(10b), R^(11a), R^(11b), q and m are as definedfor formula (Id); each R^(2a), R^(2b), R^(3a) and R^(3b) isindependently H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy, or is taken together with the carbon to which itis attached and a geminal R² or R³ to form a carbonyl moiety; eachR^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independently H,hydroxyl, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy, istaken together with the carbon to which it is attached and a geminal R⁸to form a cycloalkyl moiety or a carbonyl moiety, is taken together witha geminal R⁸ to form a methylene or a substituted methylene, is takentogether with a vicinal R⁸ and the carbon atoms to which they areattached to form a substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl or substituted orunsubstituted heterocyclyl moiety or is taken together with a vicinal R⁸to form a bond, provided: (i) at most one pair of vicinal R⁸ groups aretaken together to form a bond; and (ii) when an R⁸ is taken togetherwith a vicinal R⁸ to form a bond, the geminal R⁸ is other than hydroxyl;and Q is a substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl or substituted or aunsubstituted heterocyclyl, unsubstituted amino, substituted amino,alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy oracylamino; or a salt or solvate thereof.

In one variation, the compound of the invention is of the formula (Id),where each R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b), R^(11a) andR^(11b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, hydroxyl, alkoxy, cyano, nitro or is taken together with thecarbon to which it is attached to and a geminal R group to form acarbonyl moiety or a cycloalkyl moiety. In another variation, thecompound is of the formula (I), where each R^(2a), R^(2b), R^(3a) andR^(3b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, hydroxyl, alkoxy, cyano, nitro or is taken together with thecarbon to which it is attached to and a geminal R group to form acarbonyl moiety and each R^(10a), R^(10b), R^(11a) and R^(11b) isindependently H, substituted or unsubstituted C₁-C₈ alkyl or is takentogether with the carbon to which it is attached to and a geminal Rgroup to form a carbonyl moiety or a cycloalkyl moiety (e.g.cyclopropyl). In another variation, the compound is of the formula (Id),where Q is a substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl or substituted or aunsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy,aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino.

In another variation, the compound is of the formula (I), (Ia), (Ib),(Ic), (C) or (Id) or any variation thereof detailed herein where Q is asubstituted or unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkenyl, or substituted or a unsubstituted heterocyclyl, or a saltor solvate thereof. In one variation, the compound is of the formula(I), (Ia), (Ib), (Ic), (C) or (Id) or any variation thereof detailedherein, where Q is a carbocycle, such as a 5, 6 or 7 memberedcarbocycle. In one variation, the compound is of the formula (I), (Ia),(Ib), (Ic), (C) or (Id) or any variation thereof detailed herein, whereQ is a heterocycle, such as a 5, 6 or 7 membered carbocycle.

In another variation, the compound is of the formula (I), (Ia), (Ib),(Ic), (C) or (Id) or any variation thereof detailed herein where Q issubstituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, or a salt or solvate thereof. In another variation, thecompound is of the formula (I), (Ia), (Ib), (Ic), (C) or (Id) or anyvariation thereof detailed herein where Q is substituted orunsubstituted heteroaryl, such as a 5, 6 or 7 membered heteroaryl, or asalt or solvate thereof. In one variation, the compound is of theformula (I), (Ia), (Ib), (Ic), (C) or (Id) or any variation thereofdetailed herein where Q is a substituted or unsubstituted aryl, such asa 5, 6 or 7 membered aryl, or a salt or solvate thereof.

In one variation, a compound of the invention is of the formula (I),(Ia), (Ib), (Ic), (C) or (Id) or any variation thereof detailed hereinwhere: R¹ is a substituted or unsubstituted C₁-C₈ alkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl or substitutedor unsubstituted aryl; each R^(2a) and R^(2b) is independently H,methyl, fluoro or R^(2a) and R^(2b) are taken together to form acarbonyl moiety; each R^(3a) and R^(3b) is independently H or fluoro;each R^(10a) and R^(10b) is independently H, halo, hydroxyl or methyl orR^(10a) and R^(10b) are taken together to form a carbonyl, and eachR^(11a) and R^(11b) is independently H or methyl or R^(11a) and R^(11b)are taken together to form a carbonyl. This variation is referred to asformula “Ie”. All variations referring to formula (I), where applicable,may apply equally to any of formula (Ia)-(Ie) the same as if each andevery variation were specifically and individually listed.

In another variation, a compound of the invention is of the formula (I)or (Ie) where X⁷, X⁸, X⁹ and X¹⁰ are taken together to provide anaromatic moiety selected from the following structures:

where each R⁴ is as defined for formula (I) or (Ie); or in a particularvariation, where each R⁴ is independently hydroxyl, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, alkylsulfonylamino oracyl; or in still a further variation, where R⁴ is independently halo,unsubstituted C₁-C₄ alkyl or C₁-C₄ perhaloalkyl. In another variation,each R⁴ is independently halo or an unsubstituted C₁-C₈ alkyl. In oneembodiment, the foregoing rings are substituted with an (R⁴)₁substituent, such that that aromatic moiety is substituted is a singleR⁴ group, which in one variation is halo or unsubstituted C₁-C₈ alkyl.In a particular variation, R⁴ is other than H. In one such variation,the foregoing rings have (R⁴)₀ substituents, such that that aromaticmoiety is unsubstituted and contains no R⁴ groups.

In another variation, compounds of any of the foregoing formulae areprovided, where, if applicable, X⁷, X⁸, X⁹ and X¹⁰ are taken together toprovide an aromatic moiety selected from the following structures:

where each R⁴ is as defined for the formulae; or in a particularvariation, where each R⁴ is independently alkyl, perhaloalkyl or halo orin an even more particular variation, where each R⁴ is independentlymethyl, trifluoromethyl, chloro or fluoro. In one embodiment, theforegoing rings are substituted with an (R⁴)₁ substituent, such thatthat aromatic moiety is substituted is a single R⁴ group, which in onevariation is halo or unsubstituted C₁-C₈ alkyl. In a particularvariation, R⁴ is other than H. In one such variation, the foregoingrings have (R⁴)₀ substituents, such that that aromatic moiety isunsubstituted and contains no R⁴ groups.

In a further variation, compounds of any of the foregoing formulae areprovided, where, if applicable, X⁷, X⁸, X⁹ and X¹⁰ are taken together toprovide a structure of the following formulae, where R⁴ may be asdefined in any variation hereinabove:

In one such variation, R⁴ is halo or an unsubstituted C₁-C₈ alkyl.

In a particular embodiment, the compound is of the formula (I), (Ia),(Ib), (Ic) or (C) or any variation thereof detailed herein where X⁷, X⁸,X⁹ and X¹⁰ are CR⁴. In another embodiment, the compound is of theformula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailedherein where at least one of X⁷, X⁸, X⁹ and X¹⁰ is N. Another variationprovides a compound of the formula (I), (Ia), (Ib), (Ic) or (C) or anyvariation thereof detailed herein where at least two of X⁷, X⁸, X⁹ andX¹⁰ are N. A further variation provides a compound of the formula (I),(Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein where 2of X⁷, X⁸, X⁹ and X¹⁰ are N and 2 of X⁷, X⁸, X⁹ and X¹⁰ are CR⁴. Acompound of the formula (I), (Ia), (Ib), (Ic) or (C) or any variationthereof detailed herein where 1 of X⁷, X⁸, X⁹ and X¹⁰ is N and 3 of X⁷,X⁸, X⁹ and X¹⁰ are CR⁴ is also embraced by this invention.

In still a further variation, a compound of the invention is of theformula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailedherein where X⁷, X⁸, X⁹ and X¹⁰ are taken together to provide anaromatic moiety selected from the following structures:

wherein R⁴ is as defined in formula (I); or in a particular variation,where R⁴ is hydroxyl, halo, C₁-C₈ perhaloalkyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,C₁-C₈ alkoxy, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino,alkylsulfonylamino or acyl; or in still a further variation, where eachR⁴ is independently halo, unsubstituted C₁-C₄ alkyl or C₁-C₄perhaloalkyl. In another variation, R⁴ is halo or unsubstituted C₁-C₈alkyl. In yet another variation, compounds of any of the foregoingformulae are provided, where, if applicable, X⁷, X⁸, X⁹ and X¹⁰ aretaken together to provide a structure of the formula:

In a particular variation, a compound of the invention is of the formula(I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed hereinwhere X⁷, X⁸, X⁹ and X¹⁰ are taken together to provide

In still a further variation, compounds of any of the foregoing formulaeare provided, where, if applicable, X⁷, X⁸, X⁹ and X¹⁰ are takentogether provide an aromatic moiety selected from the followingstructures:

wherein R⁴ is as defined in the formulae or in any particular variationherein, such as when each R⁴ is independently alkyl or halo or in aneven more particular variation, where each R⁴ is independently methyl,chloro, iodo or fluoro.

In yet another variation, compounds of any of the foregoing formulae areprovided, where, if applicable, X⁷, X⁸, X⁹ and X¹⁰ are taken togetherprovide an aromatic moiety selected from the following structures:

In another embodiment, a compound of the invention is of the formula(I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein,wherein X⁷-X¹⁰ are as defined in formula (I), (Ia), (Ib), (Ic) or (C) orany variation thereof detailed herein or as detailed in any variationherein, where R¹ is H, substituted or unsubstituted C₁-C₈ alkyl, acyl,acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl. In a furtherembodiment, a compound of the invention is of the formula (I), (Ia),(Ib), (Ic) or (C) or any variation thereof detailed herein, whereinX⁷-X¹⁰ are as defined in formula (I) or as detailed in any variationherein, where R¹ is a substituted or unsubstituted C₁-C₈ alkyl, acyl,acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl orsubstituted or unsubstituted aryl. In a particular variation, a compoundof the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or anyvariation thereof detailed herein, wherein X⁷-X¹⁰ are as defined informula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailedherein, where R¹ is methyl, ethyl, cyclopropyl, propylate,trifluoromethyl, isopropyl, tert-butyl, sec-butyl, 2-methylbutyl,propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal, 2-hydroxyethyl,2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl,cyclohexyl, substituted phenyl, piperidin-4-yl, hydroxycyclopent-3-yl,hydroxycyclopent-2-yl, hydroxycycloprop-2-yl,1-hydroxy-1-methylcycloprop-2-yl, or1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl.

In another variation, the compound of the invention is of the formula(I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein,where X⁷-X¹⁰ and R¹ are as defined in formula (I), (Ia), (Ib), (Ic) or(C) or any variation thereof detailed herein, where R^(2a) and R^(2b)are independently H, substituted or unsubstituted C₁-C₈ alkyl, halo,cyano, nitro or R^(2a) and R^(2b) are taken together to form a carbonylmoiety and each R^(3a) and R^(3b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano or nitro. In another variation,the compound of the invention is of the formula (I), (Ia), (Ib), (Ic) or(C) or any variation thereof detailed herein, where X⁷-X¹⁰ and R¹ are asdefined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereofdetailed herein, where each R^(2a) and R^(2b) is independently H,unsubstituted C₁-C₈ alkyl, halo or R^(2a) and R^(2b) are taken togetherto form a carbonyl moiety and each R^(3a) and R^(3b) is independently H,unsubstituted C₁-C₈ alkyl, halo or R^(3a) and R^(3b) are taken togetherto form a carbonyl moiety. The invention also embraces compounds of theinvention according to formula (I), where X⁷-X¹⁰ and R¹ are as definedin formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereofdetailed herein, where each R^(2a) and R^(2b) is independently H,methyl, halo or R^(2a) and R^(2b) are taken together to form a carbonylmoiety and each R^(3a) and R^(3b) is independently H, methyl, halo orR^(3a) and R^(3b) are taken together to form a carbonyl moiety. Theinvention further embraces compounds of the invention according toformula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailedherein, where X⁷-X¹⁰ and R¹ are as defined in formula (I), (Ia), (Ib),(Ic) or (C) or any variation thereof detailed herein, where each ofR^(2a), R^(2b), R^(3a) and R^(3b) is H. In one variation, a compound ofthe invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or anyvariation thereof detailed herein where X⁷-X¹⁰ and R¹ are as defined informula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailedherein, where at least one of R^(2a), R^(2b), R^(3a) and R^(3b) is asubstituted or unsubstituted C₁-C₈ alkyl, halo, cyano, nitro or is takentogether with the carbon to which it is attached and a geminal R² or R³to form a carbonyl moiety. In another variation, a compound of theinvention is of the formula (I), (Ia), (Ib), (Ic) or (C) or anyvariation thereof detailed herein where X⁷-X¹⁰ and R¹ are as defined informula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailedherein, where at least two of R^(2a), R^(2b), R^(3a) and R^(3b) is asubstituted or unsubstituted C₁-C₈ alkyl, halo, cyano, nitro or is takentogether with the carbon to which it is attached and a geminal R² or R³to form a carbonyl moiety. In yet another variation, a compound of theinvention is of the formula (I), (Ia), (Ib), (Ic) or (C) or anyvariation thereof detailed herein where X⁷-X¹⁰ and R¹ are as defined informula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailedherein, where at least one of R^(2a), R^(2b), R^(3a) and R^(3b) isfluoro or methyl or is taken together with the carbon to which it isattached and a geminal R² or R³ to form a carbonyl moiety. In stillanother variation, a compound of the invention is of the formula (I),(Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein whereX⁷-X¹⁰ and R¹ are as defined in formula (I), (Ia), (Ib), (Ic) or (C) orany variation thereof detailed herein, where either R^(2a) and R^(2b) orR^(3a) and R^(3b) are each methyl or fluoro (e.g., both R^(2a) andR^(2b) are methyl or one is fluoro and one is methyl) or are takentogether to form a carbonyl moiety. In one variation, R^(2a) and R^(2b)are taken together to form a carbonyl moiety. In another variation, atleast one of R^(2a) and R^(2b) is hydroxyl or alkoxy. In a particularvariation, each R^(2a) and R^(2b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, nitro or R^(2a) and R^(2b) aretaken together to form a carbonyl. In another variation, when X¹ is N,each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro or R^(2a) and R^(2b) are taken togetherto form a carbonyl.

The invention also embraces compounds according to formula (I), (Ia),(Ib), (Ic) or (C) or any variation thereof detailed herein, whereX⁷-X¹⁰, R¹, R^(2a), R^(2b), R^(3a) and R^(3b) are as defined in formula(I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein,where each R^(10a) and R^(10b) is independently H, halo, anunsubstituted C₁-C₈ alkyl, hydroxyl or R^(10a) and R^(10b) are takentogether to form a cycloalkyl or a carbonyl. Also embraced are compoundsaccording to formula (I), (Ia), (Ib), (Ic) or (C) or any variationthereof detailed herein, where X⁷-X¹⁰, R¹, R^(2a), R^(2b), R^(3a) andR^(3b) are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or anyvariation thereof detailed herein or as detailed in any variationherein, where each R^(10a) and R^(10b) is independently H, halo, anunsubstituted C₁-C₄ alkyl, hydroxyl or R^(10a) and R^(10b) are takentogether to form a cycloalkyl or a carbonyl. In another variation, acompound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C)or any variation thereof detailed herein, where X⁷-X¹⁰, R¹, R^(2a),R^(2b), R^(3a) and R^(3b) are as defined in formula (I), (Ia), (Ib),(Ic) or (C) or any variation thereof detailed herein, where each R^(10a)and R^(10b) is independently H, bromo, methyl, hydroxyl or R^(10a) andR^(10b) are taken together to form a cyclopropyl or a carbonyl. In yetanother variation, a compound of the invention is of the formula (I),(Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, whereX⁷-X¹⁰, R¹, R^(2a), R^(2b), R^(3a) and R^(3b) are as defined in formula(I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein,where at least one of R^(10a) and R^(10b) is an unsubstituted C₁-C₈alkyl, hydroxyl, halo or R^(10a) and R^(10b) are taken together to forma cycloalkyl or a carbonyl. In still a further variation, a compound ofthe invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or anyvariation thereof detailed herein, where X⁷-X¹⁰, R¹, R^(2a), R^(2b),R^(3a) and R^(3b) are as defined in formula (I), (Ia), (Ib), (Ic) or (C)or any variation thereof detailed herein, where at least one of R^(10a)and R^(10b) is methyl, bromo, hydroxyl or R^(10a) and R^(10b) are takentogether to form a cyclopropyl or a carbonyl. In another variation, acompound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C)or any variation thereof detailed herein, where X⁷-X¹⁰, R¹, R^(2a),R^(2b), R^(3a) and R^(3b) are as defined in formula (I), (Ia), (Ib),(Ic) or (C) or any variation thereof detailed herein, where both R^(10a)and R^(10b) are methyl. In another variation, a compound of theinvention is of the formula (I), (Ia), (Ib), (Ic) or (C) or anyvariation thereof detailed herein, where X⁷-X¹⁰, R¹, R^(2a), R^(2b),R^(3a) and R^(3b) are as defined in formula (I), (Ia), (Ib), (Ic) or (C)or any variation thereof detailed herein, where R^(10a) and R^(10b) aretaken together to form a carbonyl. In another variation, a compound ofthe invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or anyvariation thereof detailed herein, where X⁷-X¹⁰, R¹, R^(2a), R^(2b),R^(3a) and R^(3b) are as defined in formula (I), (Ia), (Ib), (Ic) or (C)or any variation thereof detailed herein, where R^(10a) is H and R^(10b)is methyl. In another variation, a compound of the invention is of theformula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailedherein, where X⁷-X¹⁰, R¹, R^(2a), R^(2b), R^(3a) and R^(3b) are asdefined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereofdetailed herein, where R^(10a) is H and R^(10b) is bromo. When thecarbon of formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereofdetailed herein bearing R^(10a) and R^(10b) is optically active, it maybe in the S or R configuration and compositions comprising substantiallypure R or S compound or mixtures thereof in any amount are embraced bythis invention.

The invention also embraces compounds according to formula (I), (Ia),(Ib), (Ic) or (C) or any variation thereof detailed herein, whereX⁷-X¹⁰, R¹, R^(2a), R^(2b), R^(3a) and R^(3b) are as defined in formula(I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein,where each R^(11a) and R^(11b) is independently H, halo, anunsubstituted C₁-C₈ alkyl, hydroxyl or R^(11a) and R^(11b) are takentogether to form a cycloalkyl or a carbonyl. Also embraced are compoundsaccording to formula (I), (Ia), (Ib), (Ic) or (C) or any variationthereof detailed herein, where X⁷-X¹⁰, R¹, R^(2a), R^(2b), R^(3a) andR^(3b) are as defined in formula (I), (Ia), (Ib), (Ic) or (C) or anyvariation thereof detailed herein or as detailed in any variationherein, where each R^(11a) and R^(11b) is independently H, halo, anunsubstituted C₁-C₄ alkyl, hydroxyl or R^(11a) and R^(11b) are takentogether to form a cycloalkyl or a carbonyl. In another variation, acompound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C)or any variation thereof detailed herein, where X⁷-X¹⁰, R¹, R^(2a),R^(2b), R^(3a) and R^(3b) are as defined in formula (I), (Ia), (Ib),(Ic) or (C) or any variation thereof detailed herein, where each R^(11a)and R^(11b) is independently H, bromo, methyl, hydroxyl or R^(11a) andR^(11b) are taken together to form a cyclopropyl or a carbonyl. In yetanother variation, a compound of the invention is of the formula (I),(Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, whereX⁷-X¹⁰, R¹, R^(2a), R^(2b), R^(3a) and R^(3b) are as defined in formula(I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein,where at least one of R^(11a) and R^(11b) is an unsubstituted C₁-C₈alkyl, hydroxyl, halo or R^(1la) and R^(11b) are taken together to forma cycloalkyl or a carbonyl. In still a further variation, a compound ofthe invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or anyvariation thereof detailed herein, where X⁷-X¹⁰, R¹, R^(2a), R^(2b),R^(3a) and R^(3b) are as defined in formula (I), (Ia), (Ib), (Ic) or (C)or any variation thereof detailed herein, where at least one of R^(11a)and R^(11b) is methyl, bromo, hydroxyl or R^(11a) and R^(11b) are takentogether to form a cyclopropyl or a carbonyl. In another variation, acompound of the invention is of the formula (I), (Ia), (Ib), (Ic) or (C)or any variation thereof detailed herein, where X⁷-X¹⁰, R¹, R^(2a),R^(2b), R^(3a) and R^(3b) are as defined in formula (I), (Ia), (Ib),(Ic) or (C) or any variation thereof detailed herein, where both R^(11a)and R^(11b) are methyl. In another variation, a compound of theinvention is of the formula (I), (Ia), (Ib), (Ic) or (C) or anyvariation thereof detailed herein, where X⁷-X¹⁰, R¹, R^(2a), R^(2b),R^(3a) and R^(3b) are as defined in formula (I), (Ia), (Ib), (Ic) or (C)or any variation thereof detailed herein, where R^(11a) and R^(11b) aretaken together to form a carbonyl. In another variation, a compound ofthe invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or anyvariation thereof detailed herein, where X⁷-X¹⁰, R¹, R^(2a), R^(2b),R^(3a) and R^(3b) are as defined in formula (I), (Ia), (Ib), (Ic) or (C)or any variation thereof detailed herein, where R^(11a) is H and R^(11b)is methyl. In another variation, a compound of the invention is of theformula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailedherein, where X⁷-X¹⁰, R¹, R^(2a), R^(2b), R^(3a) and R^(3b) are asdefined in formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereofdetailed herein, where R^(11a) is H and R^(11b) is bromo. When thecarbon of formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereofdetailed herein bearing R^(11a) and R^(11b) is optically active, it maybe in the S or R configuration and compositions comprising substantiallypure R or S compound or mixtures thereof in any amount are embraced bythis invention.

In a particular variation, a compound of the invention is of the formula(I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed hereinwhere R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10a), R^(10b),R^(11a) and R^(11b) are taken together to form a ring selected from thestructures:

where R¹ in the structures above is as defined for formula (I), (Ia),(Ib), (Ic) or (C) or any particular variation detailed herein.

Compounds of the formulae (II-1), (II-2), (II-3), (II-4), (II-5),(II-6), (II-7) and (II-8) are also embraced by this invention:

where in each of (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7)and (II-8), R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b),R^(11a), R^(11b), R^(8a)-R^(8f), m, q and Q are as described for formula(I), (Ia), (Ib), (Ic) or (C) or any applicable variation thereof.

Compounds of the formulae (III-1), (III-2), (III-3), (III-4), (III-5),(III-6), (III-7), (III-8), (III-9), (III-10), (III-11), (III-12),(III-13), (III-14) and (III-15) are further embraced this invention:

where in each of formulae (III-1), (III-2), (III-3), (III-4), (III-5),(III-6), (III-7), (III-8), (III-9), (III-10), (III-11), (III-12),(III-13), (III-14) and (III-15), R¹, R⁴, R^(2a), R^(2b), R^(3a), R^(3b),R^(10a), R^(10b), R^(11a), R^(11b), R^(8a)—R^(8f), m, q and Q are asdescribed for formula (I), (Ia), (Ib), (Ic) or (C) or any applicablevariation thereof.

Compounds of the formulae (IV-1), (IV-2), (IV-3), (IV-4), (IV-5),(IV-6), (IV-7), (IV-8) and (IV-9) are further embraced by thisinvention:

where in each of formulae (IV-1), (IV-2), (IV-3), (IV-4), (IV-5),(IV-6), (IV-7), (IV-8) and (IV-9), R¹, R⁴, R^(2a), R^(2b), R^(3a),R^(3b), R^(10a), R^(10b), R^(11a), R^(11b), R^(8a)—R^(8f), m, q and Qare as described for formula (I), (Ia), (Ib), (Ic) or (C) or anyapplicable variation thereof.

The invention also embraces compounds of the formulae (V-1), (V-2),(V-3), (V-4), (V-5), (V-6), (V-7), (V-8), (V-9), (V-10), (V-11), (V-12),(V-13), (V-14), (V-15), (V-16), (V-17), (V-18), (V-19), (V-20), (V-21),(V-22), (V-23), (V-24), (V-25), (V-26) and (V-27) are also embraced bythis invention:

where in each of formulae (V-1), (V-2), (V-3), (V-4), (V-5), (V-6),(V-7), (V-8), (V-9), (V-10), (V-11), (V-12), (V-13), (V-14), (V-15),(V-16), (V-17), (V-18), (V-19), (V-20), (V-21), (V-22), (V-23), (V-24),(V-25), (V-26) and (V-27), R¹, R⁴, R^(2a), R^(2b), R^(3a), R^(3b),R^(10a), R^(10b), R^(11a), R^(11b), R^(8a)—R^(8f), m, q and Q are asdescribed for formula (I), (Ia), (Ib), (Ic) or (C) or any applicablevariation thereof.

The invention embraces a compound according to formula (I), (Ia), (Ib)or (Ic) or any variation thereof detailed herein, or a compoundaccording to any one of the formulae (II-1)-(II-8), (III-1)-(III-15),(IV-1)-(IV-9) or (V-1)-(V-27), where each R^(8a), R^(8b), R^(8c),R^(8d), R^(8e) and R^(8f) is independently H, hydroxyl, C₁-C₈ alkyl,C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy, is taken together with thecarbon to which it is attached and a geminal R⁸ to form a cycloalkylmoiety or a carbonyl moiety, is taken together with a geminal R⁸ to forma methylene or a substituted methylene, is taken together with a vicinalR⁸ and the carbon atoms to which they are attached to form a substitutedor unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or istaken together with a vicinal R⁸ to form a bond, provided: (i) at mostone pair of vicinal R⁸ groups are taken together to form a bond; and(ii) when an R⁸ is taken together with a vicinal R⁸ to form a bond, thegeminal R⁸ is other than hydroxyl. In one variation, a compound of theinvention is of the formula (I), (Ia), (Ib) or (Ic) or any variationthereof detailed herein, or is of any one of the formulae (II-1)-(II-8),(III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where each R^(8a),R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independently H, hydroxyl,unsubstituted C₁-C₄ alkyl or is taken together with the carbon to whichit is attached and a geminal R⁸ to form a cycloalkyl moiety. In onevariation, a compound of the invention is of the formula (I), (Ia), (Ib)or (Ic) or any variation thereof detailed herein, or is of any one ofthe formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or(V-1)-(V-27), where at least one of R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) is taken together with the carbon to which it isattached and a geminal R⁸ to form a carbonyl moiety. In anothervariation, a compound of the invention is of the formula (I), (Ia), (Ib)or (Ic) or any variation thereof detailed herein, or is of any one ofthe formulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or(V-1)-(V-27), where each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) andR^(8f) is independently H, hydroxyl, methyl or is taken together withthe carbon to which it is attached and a geminal R⁸ to form acyclopropyl moiety. In one variation, a compound of the invention is ofthe formula (I), (Ia), (Ib) or (Ic) or any variation thereof detailedherein, or is of any one of the formulae (II-1)-(II-8),(III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where at least one ofR^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is taken together witha geminal R⁸ to form a methylene (CH₂═) or a substituted methylene suchas CH₃CH═ or the like. In another variation, a compound of the inventionis of the formula (I), (Ia), (Ib) or (Ic) or any variation thereofdetailed herein, or is of any one of the formulae (II-1)-(II-8),(III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where at least one ofR^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is taken together witha vicinal R⁸ to form a bond, where the resultant double bond is in E- orZ-configuration. In one variation, a compound of the invention is of theformula (I), (Ia), (Ib) or (Ic) or any variation thereof detailedherein, or is of any one of the formulae (II-1)-(II-8),(III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where at least one ofR^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is taken together witha vicinal R⁸ and the carbons to which they are attached to form asubstituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₃-C₈ cycloalkenyl or substituted or unsubstitutedheterocyclyl moiety. In one variation, a compound of the invention is ofthe formula (I), (Ia), (Ib) or (Ic) or any variation thereof detailedherein, or is of any one of the formulae (II-1)-(II-8),(III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where at least one ofR^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is taken together witha vicinal R⁸ and the carbons to which they are attached to form a C₃-C₈cycloalkyl. In one variation, a compound of the invention is of theformula (I), (Ia), (Ib) or (Ic) or any variation thereof detailedherein, or is of any one of the formulae (II-1)-(II-8),(III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where R^(8c), R^(8d)and the carbon to which they are attached are taken together with twoother R⁸ groups that are geminal to each other and the carbon to whichthey are attached to form a C₃-C₈ cycloalkenyl. In yet anothervariation, a compound of the invention is of the formula (I), (Id) or(Ie) or any variation thereof detailed herein, or is any one of theformulae (II-1)-(II-8), (III-1)-(II-15), (IV-1)-(IV-9) or (V-1)-(V-27),where wherein q is 0 and m is 1. The invention also embraces a compoundof the invention according to formula (I), (Id) or (Ie) or any variationthereof detailed herein, or a compound according to any one of theformulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27),where q and m are both 0.

In certain embodiments, compounds of formulae detailed herein areprovided where R¹ is selected from the following moieties:

The invention further embraces a compound according to formula (I),(Ia), (Ib) or (Ic) or any variation thereof detailed herein, or acompound according to any one of the formulae (II-1)-(II-8),(III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where q, m, R^(8a),R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) are taken together to form amoiety selected from the group consisting of the structures:

The invention further embraces a compound according to formula (A) or(A-1) or any variation thereof detailed herein, where q, m, R^(8a),R^(8b), R^(8c), R^(8d), R^(8g) and R^(8h) are taken together with thecarbons to which they are attached to form a moiety selected from thegroup consisting of the structures:

The invention further embraces a compound according to formula (I),(Ia), (Ib) or (Ic) or any variation thereof detailed herein, or acompound according to any one of the formulae (II-1)-(II-8),(III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where R^(8c), R^(8d)and the carbon to which they are attached are taken together withR^(8e), R^(8f) and the carbon to which they are attached or R^(8a),R^(8b) and the carbon to which they are attached to form a moietyselected from the group consisting of the structures, each of which maybe optionally substituted, where each R⁸ is independently H, hydroxyl,C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy or carbonylalkoxy:

In another variation, a compound of the invention is of the formula (I),(Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or acompound according to any one of the formulae (III-1)-(III-15),(IV-1)-(IV-9) or (V-1)-(V-27), where each R⁴ is independently H, halo,substituted or unsubstituted C₁-C₈ alkyl, C₁-C₈ perhaloalkyl,substituted or unsubstituted heterocyclyl or a substituted orunsubstituted aryl. In yet another variation, a compound of theinvention is of the formula (I), (Ia), (Ib), (Ic) or (C) or anyvariation thereof detailed herein, or a compound according to any one ofthe formulae (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where eachR⁴ is independently H or a substituted or unsubstituted C₁-C₈ alkyl. Instill another variation, a compound of the invention is of the formula(I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein,or a compound according to any one of the formulae (III-1)-(III-15),(IV-1)-(IV-9) or (V-1)-(V-27), where each R⁴ is H. The invention alsoembraces compounds of the formula (I), (Ia), (Ib), (Ic) or (C) or anyvariation thereof detailed herein, or a compound according to any one ofthe formulae (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27), where eachR⁴ is independently H, halo, unsubstituted C₁-C₄ alkyl, C₁-C₄perhaloalkyl or a substituted or unsubstituted aryl. The inventionfurther embraces compounds of the formula (I), (Ia), (Ib), (Ic) or (C)or any variation thereof detailed herein, or a compound according to anyone of the formulae (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27)where each R⁴ is independently H, halo, methyl, trifluoromethyl orcyclopropyl.

The invention also embraces compounds of the formula (I), (Ia), (Ib),(Ic) or (C) or any variation thereof detailed herein, or a compoundaccording to any one of the formulae (II-1)-(II-8), (III-1)-(III-15),(IV-1)-(IV-9) or (V-1)-(V-27) where Q is a substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, which may be but is notlimited to a substituted or unsubstituted pyridyl, phenyl, pyrimidinyl,pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group. In onevariation, a compound of the invention is of the formula (I), (Ia),(Ib), (Ic) or (C) or any variation thereof detailed herein, or acompound according to any one of the formulae (II-1)-(II-8),(III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a substitutedor unsubstituted phenyl or pyridyl group. In a particular variation, Qis a phenyl or pyridyl group substituted with at least one methyl group.In another variation, a compound of the invention is of the formula (I),(Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or acompound according to any one of the formulae (II-1)-(II-8),(III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a pyridyl,phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl orthiophenyl group substituted with at least one substituted orunsubstituted C₁-C₈ alkyl, halo or perhaloalkyl moiety. In still anothervariation, a compound of the invention is of the formula (I), (Ia),(Ib), (Ic) or (C) or any variation thereof detailed herein, or acompound according to any one of the formulae (II-1)-(II-8),(III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a substitutedor unsubstituted cycloalkyl or a substituted or unsubstitutedheterocyclyl. In yet another variation, a compound of the invention isof the formula (I), (Ia), (Ib), (Ic) or (C) or any variation thereofdetailed herein, or a compound according to any one of the formulae(II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Qis a substituted or unsubstituted pyridyl, phenyl, pyrazinyl,piperazinyl, pyrrolidinyl or thiomorpholinyl group. In a particularvariation, Q is a pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinylor thiomorpholinyl group substituted with at least one methyl or halogroup. In one variation, a compound of the invention is of the formula(I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein,or a compound according to any one of the formulae (II-1)-(II-8),(III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is anunsubstituted cycloalkyl or an unsubstituted heterocyclyl. In anothervariation, a compound of the invention is of the formula (I), (Ia),(Ib), (Ic) or (C) or any variation thereof detailed herein, or acompound according to any one of the formulae (II-1)-(II-8),(III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a substitutedor unsubstituted cyclohexyl, morpholinyl, piperazinyl, thiomorpholinyl,cyclopentyl or pyrrolidinyl moiety. In yet another variation, a compoundof the invention is of the formula (I), (Ia), (Ib), (Ic) or (C) or anyvariation thereof detailed herein or (Ie) or any variation of theforegoing detailed herein, or a compound according to any one of theformulae (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27)where Q is a substituted cyclohexyl, morpholinyl, piperazinyl,thiomorpholinyl, cyclopentyl or pyrrolidinyl moiety substituted with atleast one carbonyl, hydroxymethyl, methyl or hydroxyl group.

In another variation, the compound is of the formula (I), (Id),(II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) whereineach m and q is 0. In another variation, the compound is of the formula(I), (Id), (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or(V-1)-(V-27) wherein each m and q is 1. In another variation, thecompound is of the formula (I), (Id), (II-1)-(II-8), (III-1)-(III-15),(IV-1)-(IV-9) or (V-1)-(V-27) wherein m=1 and q=0.

In another variation, the compound is of the formula (I), (Id),(II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) or anyapplicable variation thereof, Q is a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted oran unsubstituted heterocyclyl, or a salt or solvate thereof. In onevariation, the compound is of the formula (I), (Id), (II-1)-(II-8),(III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) or any applicablevariation thereof, Q is a carbocycle, such as a 5, 6 or 7 memberedcarbocycle. In one variation, the compound is of the formula (I), (Id),(II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) or anyapplicable variation thereof, Q is a heterocycle, such as a 5, 6 or 7membered carbocycle.

In another variation, the compound is of the formula (I), (Id),(II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) or anyapplicable variation thereof, Q is substituted or unsubstituted aryl ora substituted or unsubstituted heteroaryl, or a salt or solvate thereof.In another variation, the compound is of the formula (I), (Id),(II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) or anyapplicable variation thereof, Q is substituted or unsubstitutedheteroaryl, such as a 5, 6 or 7 membered heteroaryl, or a salt orsolvate thereof. In one variation, the compound is of the formula (I),(Id), (II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) orany applicable variation thereof, Q is a substituted or unsubstitutedaryl, such as a 5, 6 or 7 membered aryl, or a salt or solvate thereof.

Q groups may be attached to the parent structure at any availableposition on the Q moiety. Thus, although specific attachment points forcertain Q moieties are depicted herein, it is understood that such Qmoieties, may also be connected to the parent structure at any availableposition. For example, if a 2-fluoro-phenyl is depicted herein, it isunderstood that other mono-fluoro-phenyls are intended, e.g.,3-fluoro-phenyl and 4-fluoro-phenyl. It is also understood that anyformula detailed herein, where applicable, may in one variation have a Qmoiety as detailed herein.

In still another variation, a compound of the invention is of theformulae or any variation of the foregoing detailed herein, where Q is amoiety selected from the structures:

wherein each R⁹ is independently a halo, cyano, nitro, perhaloalkyl,perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstitutedheterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino,sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino. Inone variation, Q is substituted with no more than one R⁹ group. Inanother variation, Q is substituted with only one R⁹ group. In onevariation, Q is substituted with two R⁹ groups. In a further variation,Q is selected from the aromatic structures detailed where the residuehas the moiety (R⁹)₀ such that Q either contains no R⁹ functionality ora moiety of the formula N—R⁹.

In still another variation, a compound of the invention is of theformula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailedherein, or a compound according to any one of the formulae(II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Qis a moiety selected from the structures:

wherein each R⁹ is independently a halo, cyano, nitro, perhaloalkyl,perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstitutedheterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino,sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino. Inone variation, Q is substituted with no more than one R⁹ group. Inanother variation, Q is substituted with only one R⁹ group. In onevariation, Q is substituted with two R⁹ groups. In a further variation,Q is selected from the aromatic structures detailed where the residuehas the moiety (R⁹)₀₋₂ such that Q either contains no R⁹ functionalityor a moiety of the formula N—R⁹.

In another variation, a compound of the invention is of the formula (I),(Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or acompound according to any one of the formulae (II-1)-(II-8),(III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a moietyselected from the structures:

and wherein R⁹ is connected to Q ortho or para to the position at whichQ is connected to the carbon bearing R^(8e) and R^(8f). In a particularvariation, Q is a structure of the formula:

and R⁹ is connected to Q para to the position at which Q is connected tothe carbon bearing R^(8e) and R^(8f). In another particular variation, Qis a structure of the formula

where each R⁹ is independently alkyl, perhaloalkyl or halo.

In another variation, a compound of the invention is of the formula (I),(Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or acompound according to any one of the formulae (II-1)-(II-8),(III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a moietyselected from the structures:

wherein each R⁹ is independently a halo, cyano, nitro, perhaloalkyl,perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,acyl, acyloxy, carbonylalkoxy, thioalkyl, alkoxy, substituted orunsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl,aminoacyl or aminocarbonylamino. In one variation, Q is substituted withno more than one R⁹ group. In another variation, Q is substituted withonly one R⁹ group. In yet another variation, Q is substituted with twoR⁹ groups. In a particular variation, Q is selected from the carbocyclicand heterocyclic structures detailed where the residue has the moiety(R⁹)₀₋₂ such that Q either contains no R⁹ functionality or a moiety ofthe formula N—R⁹.

In another variation, a compound of the invention is of the formula (I),(Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or acompound according to any one of the formulae (II-1)-(II-8),(III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a moietyselected from the structures:

wherein each R⁹ is independently a halo, cyano, nitro, perhaloalkyl,perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,acyl, acyloxy, carbonylalkoxy, thioalkyl, alkoxy, substituted orunsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl,aminoacyl or aminocarbonylamino. In one variation, Q is substituted withno more than one R⁹ group. In another variation, Q is substituted withonly one R⁹ group. In yet another variation, Q is substituted with twoR⁹ groups. In a particular variation, Q is selected from the carbocyclicand heterocyclic structures detailed where the residue has the moiety(R⁹)₀₋₂ such that Q either contains no R⁹ functionality or a moiety ofthe formula N—R⁹.

In any structure or variation detailed herein containing an R⁹ group, inone variation, each R⁹ is independently a substituted or unsubstitutedC₁-C₄ alkyl, halo, trifluoromethyl or hydroxyl. In another variation,each R⁹ is independently methyl, —CH₂OH, isopropyl, halo,trifluoromethyl or hydroxyl.

In one variation, a compound of the invention is of the formula (I),(Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or acompound according to any one of the formulae (II-1)-(II-8),(III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a moietyselected from the structures:

In another variation, a compound of the invention is of the formula (I),(Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or acompound according to any one of the formulae (II-1)-(II-8),(III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a moietyselected from the structures:

In yet another variation, a compound of the invention is of the formula(I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein,or a compound according to any one of the formulae (II-1)-(II-8),(III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a moietyselected from the structures:

In one variation, a compound of the invention is of the formula (I),(Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or acompound according to any one of the formula (I), (Id), (II-1)-(II-8),(III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a moietyselected from the structures:

In another variation, a compound of the invention is of the formula (I),(Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein, or acompound according to any one of the formula (I), (Id), (II-1)-(II-8),(III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Q is a moietyselected from the structures:

In yet another variation, a compound of the invention is of the formula(I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein,or a compound according to any one of the formula (I), (Id),(II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Qis a moiety selected from the structures:

In yet another variation, a compound of the invention is of the formula(I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein,or a compound according to any one of the formula (I), (Id),(II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Qis a moiety selected from the structures:

In yet another variation, a compound of the invention is of the formula(I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailed herein,or a compound according to any one of the formula (I), (Id),(II-1)-(II-8), (III-1)-(III-15), (IV-1)-(IV-9) or (V-1)-(V-27) where Qis a moiety selected from the structures:

In a further variation, a compound of the invention is of the formula(I), (Ia), (Ib) or (Ic) or any variation thereof detailed herein whereR¹ is an unsubstituted alkyl, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a),R^(10b), R^(11a) and R^(11b) are each H, each X⁷, X⁸, X⁹ and X¹⁰ isindependently N or CH, each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) andR^(8f) is independently H or hydroxyl, and Q is a substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, includingbut not limited to a substituted or unsubstituted phenyl or pyridylgroup. Where Q is a substituted phenyl or pyridyl group, in onevariation it is substituted with at least one methyl group.

In one variation, compounds of the formulae detailed herein areprovided, such as compounds of the formulae (I), (Ia), (Ib), (Ic) or (C)or any variation thereof detailed herein, where R¹ is selected from thefollowing moieties:

In yet a further variation, a compound of the invention is of theformula (I), (Ia), (Ib), (Ic) or (C) or any variation thereof detailedherein where R¹ is a substituted or unsubstituted C₁-C₈ alkyl, acyl,acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl; each R^(2a) and R^(2b) isindependently H, unsubstituted C₁-C₈ alkyl or halo; each R^(3a) andR^(3b) is independently H or halo; each X⁷, X⁸, X⁹ and X¹⁰ is CR⁴, whereR⁴ is as defined in formula (I), (Ia), (Ib), (Ic) or (C) or anyvariation thereof detailed herein or in a particular variation, R⁴ is H,halo, pyridyl, methyl or trifluoromethyl; each R^(10a), R^(10b), R^(11a)and R^(11b) is independently H, unsubstituted C₁-C₈ alkyl, and Q is asubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, including but not limited to a substituted or unsubstitutedpyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolylor thiophenyl group. In a particular variation, Q is a pyridyl, phenyl,pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenylgroup substituted with at least one substituted or unsubstituted C₁-C₈alkyl, halo or perhaloalkyl moiety. In one variation, a compound of thevariation detailed herein is provided wherein R¹ is propylate, methyl,ethyl, cyclopropyl, trifluoromethyl, isopropyl, tert-butyl, sec-butyl,2-methylbutyl, propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal,2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl,cyclopentyl, cyclohexyl, substituted phenyl, piperidin-4-yl,hydroxycyclopent-3-yl, hydroxycyclopent-2-yl, hydroxycycloprop-2-yl,1-hydroxy-1-methylcycloprop-2-yl, or1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl.

In still a further variation, a compound of the invention is of theformula (I), (Ia), (Ib) or (Ic) or any variation thereof detailed hereinwhere R¹ is a substituted or unsubstituted C₁-C₈ alkyl; each R^(2a),R^(2b), R^(3a) and R^(3b) is independently H or halo; each R⁴ isindependently H, halo, C₁-C₈ perhaloalkyl, substituted or aunsubstituted C₁-C₈ alkyl; each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e)and R^(8f) is H; and Q is a substituted or unsubstituted cyclohexyl,morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinylmoiety. The invention also embraces a compound of the formula (I), (Ia),(Ib), (Ic) or (C) or any variation thereof detailed herein where R¹ is amethyl; at least one of X⁷, X⁸, X⁹ and X¹⁰ is CR⁴, and each R⁴ isindependently H, halo, methyl or trifluoromethyl. The invention embracescompounds where Q in any variation detailed is substituted with at leastone carbonyl, hydroxymethyl, methyl or hydroxyl group.

In a particular variation, the compound is of the formula (I), (Ia),(Ib) or (Ic) or any variation thereof detailed herein where R¹ is asubstituted or unsubstituted C₁-C₈ alkyl; each R^(2a), R^(2b), R^(3a)and R^(3b) is H; each R⁴ is independently H, halo or substituted orunsubstituted C₁-C₈ alkyl; each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e)and R^(8f) is H; each R^(10a), R^(10b), R^(11a) and R^(11b) isindependently H, unsubstituted C₁-C₈ alkyl, fluoro or R^(10a) andR^(10b) are taken together to form a carbonyl or R^(11a) and R^(11b) aretaken together to form a carbonyl. In one aspect of this variation, Qmay be a substituted or unsubstituted pyridyl, phenyl, pyrazinyl,piperazinyl, pyrrolidinyl or thiomorpholinyl group. In another aspect ofthis variation, Q is a pyridyl, phenyl, pyrazinyl, piperazinyl,pyrrolidinyl or thiomorpholinyl group substituted with at least onemethyl or halo group. In another aspect of this variation, Q is asubstituted amino, alkoxy or substituted alkoxy. In yet another aspectof this variation, X⁷, X⁸, X⁹ and X¹⁰ are CR⁴ and each R⁴ isindependently H, halo or methyl.

Examples of compounds according to the invention are depicted in Table2. The compounds depicted may be present as salts even if salts are notdepicted and it is understood that the invention embraces all salts andsolvates of the compounds depicted here, as well as the non-salt andnon-solvate form of the compound, as is well understood by the skilledartisan.

TABLE 2 Representative Compounds According to the Invention. No.Structure  1

 2

 3

 4

 5

 6

 7

 8

 9

 10

 11

 12

 13

 14

 15

 16

 17

 18

 19

 20

 21

 22

 23

 24

 25

 26

 27

 28

 29

 30

 31

 32

 33

 34

 35

 36

 37

 38

 39

 40

 41

 42

 43

 44

 45

 46

 47

 48

 49

 50

 51

 52

 53

 54

 55

 56

 57

 58

 59

 60

 61

 62

 63

 64

 65

 66

 67

 68

 69

 70

 71

 72

 73

 74

 75

 76

 77

 78

 79

 80

 81

 82

 83

 84

 85

 86

 87

 88

 89

 90

 91

 92

 93

 94

 95

 96

 97

 98

 99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

Additional compounds of the invention are provided by formulae(J-1)-(J-11) as detailed below

Compounds of the formula (J-1) are provided:

wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each Z¹, Z², Z³ and Z⁴ is independently N or CR²;

each R² is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

X is H, OH, substituted or unsubstituted C₁-C₈ alkyl or is takentogether with Y to form a moiety of the formula —OCH₂CH₂O—, or is takentogether with Y and the carbon to which they are attached to form acyclopropyl moiety;

Y is halo, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, unsubstituted C₁-C₈ alkyl, C₁-C₈ alkylsubstituted with a carbonylalkoxy, carboxyl or acylamino moiety,substituted or unsubstituted C₃-C₆ cycloalkyl, or is taken together withX to form a moiety of the formula —OCH₂CH₂O—, or is taken together withX and the carbon to which they are attached to form a cyclopropylmoiety; and

R³ is acylamino, carbonylalkoxy, acyloxy, aminoacyl oraminocarbonylalkoxy, provided that when R³ is carbonylalkoxy, Y is halo,unsubstituted C₁-C₈ alkyl, C₁-C₈ alkyl substituted with acarbonylalkoxy, carboxyl or acylamino moiety, substituted orunsubstituted C₃-C₆ cycloalkyl, or is taken together with X to form amoiety of the formula —OCH₂CH₂O—, or is taken together with X and thecarbon to which they are attached to form a cyclopropyl moiety;

or a salt or solvate thereof.

In one variation, the salt of formula (J-1) is a pharmaceuticallyacceptable salt.

In one variation of formula (J-1), Z¹, Z², Z³ and Z⁴ are each CR² andthe compound is of the formula (J-2):

where R¹, R², R³, X and Y are as defined for formula (J-1). In oneaspect of formula (J-2), at least one of the R² moieties is H. Inanother aspect of formula (J-2), at least two R² moieties are H. In afurther aspect of formula (J-2), at least three R² moieties are H, suchas when (J-2) is of the formula (J-3):

In one variation of formula (J-3), R² is halo or an unsubstituted C₁-C₈alkyl, such as when R² is chloro or methyl. In one aspect, compounds ofthe formula (J-3) are provided wherein the compound further has one ormore of the following structural features: (i) R¹ is a substituted orunsubstituted C₁-C₈ alkyl; (ii) R³ is an acylamino, carbonylalkoxy oraminoacyl moiety; (iii) X is H, OH, unsubstituted C₁-C₈ alkyl or istaken together with Y to form a moiety of the formula —OCH₂CH₂O—, or istaken together with Y and the carbon to which they are attached to forma cyclopropyl moiety, (iv) Y is halo, unsubstituted aryl, unsubstitutedC₁-C₈ alkyl, C₁-C₈ alkyl substituted with a carbonylalkoxy, carboxyl oracylamino moiety, substituted or unsubstituted C₃-C₆ cycloalkyl, or istaken together with X to form a moiety of the formula —OCH₂CH₂O—, or istaken together with X and the carbon to which they are attached to forma cyclopropyl moiety and (v) R² is halo or an unsubstituted C₁-C₈ alkyl.In a particular variation, compounds of the formula (J-3) are providedwherein at least two of provisions (i)-(v) apply. In a particularvariation, compounds of the formula (J-3) are provided wherein at leastthree of provisions (i)-(v) apply. In a particular variation of formula(J-3), X and Y are as defined in provisions (iii) and (iv). In a furthersuch variation, X and Y are as defined in provisions (iii) and (iv) andat least one of provisions (i), (ii) and (v) also apply.

Compounds of the formula (J-1) where at least one of Z¹, Z², Z³ and Z⁴is N are also embraced. In one aspect, Z¹ is N. In another aspect, Z² isN. In a further aspect, Z³ is N. In yet another aspect, Z⁴ is N. Wheremore than one of Z¹, Z², Z³ and Z⁴ is N, the N atoms may be positionedat any available annular ring position. For example, when Z¹ is N, anyof Z², Z³ or Z⁴ may also be N.

In another variation of formula (J-1), (J-2) or (J-3), R¹ is asubstituted or unsubstituted C₁-C₈ alkyl. In a further variation offormula (J-1), (J-2) or (J-3), R¹ is an unsubstituted C₁-C₄ alkyl suchas methyl.

In still a further variation of formula (J-1), (J-2) or (J-3), R³ is anacylamino, carbonylalkoxy or aminoacyl moiety. In one aspect of formula(J-1), (J-2) or (J-3), when R³ is an acylamino moiety, R³ is an acyclicacylamino moiety, such as when R³ is an acyclic acylamino moiety of theformula —C(O)NR_(a)R_(b) where R_(a) is H or a C₁-C₈ substituted orunsubstituted alkyl and R_(b) is H, a C₁-C₈ substituted or unsubstitutedalkyl (e.g., methyl, ethyl, isopropyl or benzyl) or a heterocycle. Inanother aspect of formula (J-1), (J-2) or (J-3), when R³ is an acylaminomoiety, R³ is an acyclic acylamino moiety, such as when R³ is of theformula —C(O)NR_(a)R_(b) where R_(a) taken together with R_(b) and thenitrogen to which they are attached to form a 3-8 membered heterocyclicring (e.g., —C(O)(1-piperidinyl). In one aspect of formula (J-1), (J-2)or (J-3), when R³ is a carbonylalkoxy moiety, R³ is of the formula—C(O)O-alkyl (e.g., methyl, ethyl, cyclopentyl) or —C(O)O-substitutedalkyl and Y is halo, unsubstituted C₁-C₈ alkyl, C₁-C₈ alkyl substitutedwith a carbonylalkoxy, carboxyl or acylamino moiety, substituted orunsubstituted C₃-C₆ cycloalkyl, or is taken together with X to form amoiety of the formula —OCH₂CH₂O—, or is taken together with X and thecarbon to which they are attached to form a cyclopropyl moiety. Forinstance, in one variation of formula (J-1), (J-2) or (J-3), R³ is acarbonylalkoxy moiety of the formula —C(O)OR where R is a C₁-C₈substituted or unsubstituted alkyl, where in one variation thesubstitute on the C₁-C₈ substituted alkyl is one or more halo groups,such as an alkyl substituted with a perhaloalkyl moiety. Compounds ofthe formula (J-1), (J-2) or (J-3) are provided where R³ is an aminoacylmoiety of the formula —NR_(a)C(O)R_(b) where R_(a) is H and R_(b) is anunsubstituted or substituted alkyl, an unsubstituted or substitutedaryl, an unsubstituted or substituted heteroaryl, or a substituted orunsubstituted heterocyclic moiety. In one aspect of formula (J-1), (J-2)or (J-3), R³ is an aminoacyl moiety of the formula —NR_(a)C(O)R_(b)where R_(a) is H and R_(b) is a C₁-C₈ unsubstituted or substitutedalkyl; in another such aspect, R_(a) is H and R_(b) is an unsubstitutedC₁-C₄ alkyl. In another aspect of formula (J-1), (J-2) or (J-3), R³ isan aminoacyl moiety of the formula —NR_(a)C(O)R_(b) where R_(a) is H andR_(b) is an unsubstituted or substituted single ring aryl moiety, anunsubstituted or substituted single ring heteroaryl moiety, or asubstituted or unsubstituted single ring heterocyclic moiety, where theheteroaryl or heterocyclic moieties in one variation bear nitrogenheteroatoms (e.g., pyridinyl, piperidinyl).

Compounds of the formula (J-1), (J-2) or (J-3) are also provided where Xis H, OH, unsubstituted C₁-C₈ alkyl or is taken together with Y to forma moiety of the formula —OCH₂CH₂O—, or is taken together with Y and thecarbon to which they are attached to form a cyclopropyl moiety, and Y ishalo, unsubstituted aryl, unsubstituted C₁-C₈ alkyl, C₁-C₈ alkylsubstituted with a carbonylalkoxy, carboxyl or acylamino moiety,substituted or unsubstituted C₃-C₆ cycloalkyl, or is taken together withX to form a moiety of the formula —OCH₂CH₂O—, or is taken together withX and the carbon to which they are attached to form a cyclopropylmoiety. In one variation of formula (J-1), (J-2) or (J-3), X is H, OH oran unsubstituted C₁-C₈ alkyl (e.g., methyl) and Y is halo, anunsubstituted C₁-C₈ alkyl (e.g., methyl, isopropyl, n-butyl orcyclobutyl) or an unsubstituted single ring aryl moiety (e.g., phenyl).In one variation of formula (J-1), (J-2) or (J-3), X is OH and Y is anunsubstituted aryl. In one aspect, Y is phenyl. In another variation, Xis H and Y is a C₁-C₈ alkyl substituted with a carbonylalkoxy, carboxylor acylamino moiety. In one aspect, Y is a methylene substituted with acarbonylalkoxy, carboxyl or acylamino moiety. In a particular aspect, Yis a moiety selected from the following structures

where each R⁴ and R⁵ is independently an unsubstituted C₁-C₈ alkyl. Inone variation, Y is a moiety selected from the following structures

where each R⁴ and R⁵ is independently an unsubstituted C₁-C₈ alkyl and Xis H. In another variation, X is an unsubstituted C₁-C₈ alkyl and Y ishalo. In a particular aspect, Y is fluoro.

In a particular variation of formula (J-1), (J-2) or (J-3), R¹ is anunsubstituted C₁-C₄ alkyl; X is H, OH, unsubstituted C₁-C₈ alkyl or istaken together with Y to form a moiety of the formula —OCH₂CH₂O—, or istaken together with Y and the carbon to which they are attached to forma cyclopropyl moiety; Y is halo, unsubstituted aryl, unsubstituted C₁-C₈alkyl, C₁-C₈ alkyl substituted with a carbonylalkoxy, carboxyl oracylamino moiety, substituted or unsubstituted C₃-C₆ cycloalkyl, or istaken together with X to form a moiety of the formula —OCH₂CH₂O—, or istaken together with X and the carbon to which they are attached to forma cyclopropyl moiety; and R³ is an acylamino, carbonylalkoxy oraminoacyl moiety, provided that when R³ is carbonylalkoxy, Y is halo,unsubstituted C₁-C₈ alkyl, C₁-C₈ alkyl substituted with acarbonylalkoxy, carboxyl or acylamino moiety, substituted orunsubstituted C₃-C₆ cycloalkyl, or is taken together with X to form amoiety of the formula —OCH₂CH₂O—, or is taken together with X and thecarbon to which they are attached to form a cyclopropyl moiety. Inanother variation of formula (J-1), (J-2) or (J-3), R¹ is anunsubstituted C₁-C₄ alkyl; X is H, OH, unsubstituted C₁-C₈ alkyl or istaken together with Y to form a moiety of the formula —OCH₂CH₂O—, or istaken together with Y and the carbon to which they are attached to forma cyclopropyl moiety; Y is halo, unsubstituted aryl, unsubstituted C₁-C₈alkyl, C₁-C₈ alkyl substituted with a carbonylalkoxy, carboxyl oracylamino moiety, substituted or unsubstituted C₃-C₆ cycloalkyl, or istaken together with X to form a moiety of the formula —OCH₂CH₂O—, or istaken together with X and the carbon to which they are attached to forma cyclopropyl moiety; and R³ is an acylamino or aminoacyl moiety. It isunderstood that when R³ is an acylamino, carbonylalkoxy or aminoacylmoiety, R³ may be any such moiety detailed herein, including but notlimited to the moieties provided herein above. As such, it is understoodthat in one aspect, compounds of the formula (J-1), (J-2) or (J-3) areprovided wherein R¹ is an unsubstituted C₁-C₄ alkyl; X is H, OH,unsubstituted C₁-C₈ alkyl or is taken together with Y to form a moietyof the formula —OCH₂CH₂O—, or is taken together with Y and the carbon towhich they are attached to form a cyclopropyl moiety; Y is halo,unsubstituted aryl, unsubstituted C₁-C₈ alkyl, C₁-C₈ alkyl substitutedwith a carbonylalkoxy, carboxyl or acylamino moiety, substituted orunsubstituted C₃-C₆ cycloalkyl, or is taken together with X to form amoiety of the formula —OCH₂CH₂O—, or is taken together with X and thecarbon to which they are attached to form a cyclopropyl moiety; and R³is an acyclic or cyclic acylamino as detailed herein or an aminoacylmoiety of the formula —NR_(a)C(O)R_(b) where R_(a) is H and R_(b) is anunsubstituted or substituted alkyl, an unsubstituted or substitutedaryl, an unsubstituted or substituted heteroaryl, or a substituted orunsubstituted heterocyclic moiety.

In one variation of formula (J-3), R¹ is unsubstituted C₁-C₈ alkyl or aC₁-C₈ alkyl substituted with a perhaloalkyl moiety; and R² isindependently H, halo, unsubstituted C₁-C₈ alkyl or unsubstituted C₁-C₈alkoxy. In one variation of formula (J-3), R¹ is unsubstituted C₁-C₈alkyl; R² is unsubstituted C₁-C₈ alkyl, H or halo, and R³ is acylamino,carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy.

In one variation of formula (J-3), X is OH and Y is a substituted orunsubstituted C₁-C₈ alkyl. In another variation of (J-3), X is OH andthe compound is further defined by one or more of the followingstructural features: (i) Y is a substituted or unsubstituted C₁-C₈ alkyl(which in one aspect is methyl, butyl or isopropyl); (ii) R¹ and R² areindependently an unsubstituted C₁-C₈ alkyl (in one aspect both R¹ and R²are methyl); (iii) R³ is acylamino, carbonylalkoxy, acyloxy, aminoacylor aminocarbonylalkoxy. In a particular variation of formula (J-3), X isOH, Y is a substituted or unsubstituted C₁-C₈ alkyl; R¹ and R² are eachmethyl and R³ is acylamino, carbonylalkoxy, acyloxy, aminoacyl oraminocarbonylalkoxy.

In one variation of formula (J-3), X is OH and Y is H. In one variationof formula (J-3), X is OH; Y is H; and R¹ and R² are independently anunsubstituted C₁-C₈ alkyl. In a particular variation of formula (J-3), Xis OH; Y is H; R¹ and R² are independently an unsubstituted C₁-C₈ alkyl;and R³ is acylamino, carbonylalkoxy, acyloxy, aminoacyl oraminocarbonylalkoxy. In one variation of formula (J-3), X is OH; Y andH; R¹ and R² are each methyl; and R³ is acylamino, carbonylalkoxy,acyloxy, aminoacyl or aminocarbonylalkoxy. In a particular variation offormula (J-3), X is OH; Y is H; R¹ and R² are each methyl; and R³ isacylamino, carbonylalkoxy or aminoacyl.

Compounds of the formula (J-4) are detailed herein:

or a salt or solvate thereof, where R¹, R² and R³ are as defined forformula (J-1). In one variation of formula (J-4), R¹ and R² areindependently an unsubstituted C₁-C₈ alkyl. In a particular variation offormula v, R¹ and R² are independently an unsubstituted C₁-C₈ alkyl andR³ is acylamino, carbonylalkoxy, acyloxy, aminoacyl oraminocarbonylalkoxy. In one variation, R¹ and R² are each methyl and R³is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy.In another variation of formula (J-4), R¹ is an unsubstituted C₁-C₈alkyl; R² is halo or an unsubstituted C₁-C₈ alkyl and R³ is aminoacyl.In one such variation of formula (J-4), R¹ is methyl; R² is halo or aC₁-C₄ unsubstituted alkyl; and R³ is an aminoacyl of the formula—NR_(a)C(O)R_(b) where R_(a) is H and R_(b) is an unsubstituted orsubstituted alkyl, an unsubstituted or substituted aryl, anunsubstituted or substituted heteroaryl, or a substituted orunsubstituted heterocyclic moiety.

Compounds of the formula (J-5) are also detailed herein:

or a salt or solvate thereof, where R¹, R² and R³ are as defined forformula (J-1). In one variation of formula (J-5), R¹ is an unsubstitutedC₁-C₈ alkyl (e.g., methyl). In another variation of formula (J-5), R² isH, an unsubstituted C₁-C₈ alkyl (e.g., methyl) or halo (e.g., chloro).In one aspect of formula (J-5), R¹ is an unsubstituted C₁-C₈ alkyl andR² is H, an unsubstituted C₁-C₈ alkyl or halo. In another variation offormula (J-5), R₂ is a halo or an unsubstituted C₁-C₈ alkyl and R¹ is anunsubstituted C₁-C₄ alkyl. In a particular variation of formula (J-5),R¹ is methyl and R² is H, methyl or chloro. In one variation of formula(J-5), R¹ and R² are independently an unsubstituted C₁-C₈ alkyl such asmethyl. In a further variation of formula (J-5), R¹ is an unsubstitutedC₁-C₈ alkyl; R² is H, an unsubstituted C₁-C₈ alkyl or halo and R³ isacylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. Ina particular variation, compounds of formula (J-5) are provided where R¹is methyl, R² is H, methyl or chloro and R³ is acylamino,carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. In a furthervariation of formula (J-5), R¹ is an unsubstituted C₁-C₈ alkyl; R² ishalo or an unsubstituted C₁-C₈ alkyl; and R³ is an acylamino of theformula —C(O)NR_(a)R_(b) where R_(a) is H and R_(b) is an unsubstitutedC₁-C₈ alkyl.

Compounds of the formula (J-6) are also detailed herein:

or a salt or solvate thereof, where R¹, R² and R³ are as detailed forformula (J-1) and R⁴ is an unsubstituted C₁-C₈ alkyl. In one variationof formula (J-6), R¹ is an unsubstituted C₁-C₈ alkyl. In one variationof formula (J-6), R² is an unsubstituted C₁-C₈ alkyl or halo. In onevariation of formula (J-6), R¹ and R² are independently an unsubstitutedC₁-C₈ alkyl (e.g., methyl or ethyl). In one variation of formula (J-6),R¹ is an unsubstituted C₁-C₈ alkyl (e.g., methyl or ethyl) and R² is anunsubstituted C₁-C₈ alkyl or halo. In a particular variation of formula(J-6), R⁴ is an unsubstituted C₁-C₄ alkyl. In a further variation offormula (J-6), R⁴ is methyl, ethyl, propyl or butyl. In one aspect, R⁴is iso-propyl. In another aspect, R⁴ is tert-butyl. In a particularvariation of formula (J-6), R¹ is an unsubstituted C₁-C₈ alkyl; R² is anunsubstituted C₁-C₈ alkyl or halo and R⁴ is an unsubstituted C₁-C₄alkyl. In a further variation of formula (J-6), R¹ is an unsubstitutedC₁-C₈ alkyl; R² is an unsubstituted C₁-C₈ alkyl or halo; R⁴ is anunsubstituted C₁-C₄ alkyl and R³ is acylamino, carbonylalkoxy, acyloxy,aminoacyl or aminocarbonylalkoxy. In a particular variation, compoundsof formula (J-6) are provided where R¹ is methyl or ethyl, R² is methylor chloro; R⁴ is methyl, ethyl, isopropyl or tert-butyl and R³ isacylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. Ina further variation of formula (J-6), R¹ is an unsubstituted C₁-C₄alkyl; R² is an unsubstituted C₁-C₄ alkyl or halo; R⁴ is anunsubstituted C₁-C₄ alkyl; and R³ is acylamino or aminoacyl. In yet afurther variation of formula (J-6), R¹ is an unsubstituted C₁-C₄ alkyl;R² is an unsubstituted C₁-C₄ alkyl or halo; R⁴ is an unsubstituted C₁-C₄alkyl; and R³ is either an acylamino of the formula —C(O)NR_(a)R_(b)where R_(a) and R_(b) are independently an unsubstituted C₁-C₈ alkyl orR_(a) and R_(b) are taken together with the nitrogen to which they areattached to form a heterocyclic moiety or an aminoacyl.

Compounds of the formula (J-7) are also detailed herein:

or a salt of solvate thereof, where R¹, R² and R³ are as detailed forformula (J-1). In one variation of formula (J-7), R¹ is an unsubstitutedC₁-C₈ alkyl (e.g., methyl). In another variation of formula (J-7), R² isunsubstituted C₁-C₈ alkyl (e.g., methyl) or halo (e.g., chloro). In aparticular variation of formula (J-7), R¹ is an unsubstituted C₁-C₈alkyl and R² is unsubstituted C₁-C₈ alkyl or halo. In another variationof formula (J-7), R¹ and R² are independently an unsubstituted C₁-C₈alkyl (e.g., methyl). In one variation of formula (J-7), R¹ is anunsubstituted C₁-C₈ alkyl, R² is unsubstituted C₁-C₈ alkyl or halo andR³ is acylamino, carbonylalkoxy, acyloxy, aminoacyl oraminocarbonylalkoxy. In a particular variation of formula (J-7), R¹ andR² are independently an unsubstituted C₁-C₈ alkyl and R³ is acylamino,carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. In onevariation of formula (J-7), R³ is acylamino.

Compounds of the formula (J-8) are also detailed herein:

or a salt of solvate thereof, where R¹, R² and R³ are as detailed forformula (J-1) and R⁵ is an unsubstituted C₁-C₈ alkyl. In one variationof formula (J-8), R¹ is an unsubstituted C₁-C₈ alkyl (e.g., methyl orethyl). In another variation of formula (J-8), R² is unsubstituted C₁-C₈alkyl (e.g., methyl) or halo (e.g., chloro). In a particular variationof formula (J-8), R¹ is an unsubstituted C₁-C₈ alkyl and R² isunsubstituted C₁-C₈ alkyl or halo. In another variation of formula(J-8), R¹ and R² are independently an unsubstituted C₁-C₈ alkyl. In aparticular variation of formula (J-8), R⁵ is an unsubstituted C₁-C₄alkyl. In a further variation of formula (J-8), R⁵ is methyl, ethyl,propyl or butyl. In one aspect, R⁵ is iso-propyl. In another aspect, R⁵is tert-butyl. In one variation of formula (J-8), R¹ is an unsubstitutedC₁-C₈ alkyl, R² is unsubstituted C₁-C₈ alkyl or halo and R³ isacylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. Ina further variation of formula (J-8), R¹ is an unsubstituted C₁-C₈alkyl, R² is unsubstituted C₁-C₈ alkyl or halo and R³ is acylamino, oraminoacyl.

Compounds of the formula (J-9) are also detailed herein:

or a salt or solvate thereof, where R¹, R² and R³ are as defined forformula (J-1) and R⁶ is an unsubstituted C₁-C₈ alkyl. In one variationof formula (J-9), R¹ is an unsubstituted C₁-C₈ alkyl (e.g., methyl,ethyl or isopropyl). In another variation of formula (J-9), R² isunsubstituted C₁-C₈ alkyl (e.g., methyl) or halo (e.g., chloro). In aparticular variation of formula (J-9), R¹ is an unsubstituted C₁-C₈alkyl and R² is unsubstituted C₁-C₈ alkyl or halo. In another variationof formula (J-9), R¹ and R² are independently an unsubstituted C₁-C₈alkyl. In a particular variation of formula (J-9), R⁶ is anunsubstituted C₁-C₄ alkyl. In a further variation of formula (J-9), R⁶is methyl, ethyl, propyl or butyl. In one aspect, R⁶ is iso-propyl. Inanother aspect, R⁶ is tert-butyl. In one variation of formula (J-9), R¹is an unsubstituted C₁-C₈ alkyl, R² is unsubstituted C₁-C₈ alkyl or haloand R³ is acylamino, carbonylalkoxy, acyloxy, aminoacyl oraminocarbonylalkoxy.

Compounds of the formula (J-10) are also detailed herein:

or a salt or solvate thereof, where R¹, R² and R³ are as defined forformula (J-1). In one variation of formula (J-10), R¹ and R² are each anunsubstituted C₁-C₈ alkyl group. In another variation of formula (J-10),R¹ and R² are each an unsubstituted C₁-C₈ alkyl group and R³ isacylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. Inanother variation of formula (J-10), R¹ is an unsubstituted C₁-C₈ alkyl;R² is an unsubstituted C₁-C₈ alkyl or halo and R³ is acylamino oraminoacyl.

Compounds of the formula (J-11) are also detailed herein:

wherein:

each Z¹, Z², Z³ and Z⁴ is independently N or CR²

each R² is independently H, halo, unsubstituted C₁-C₈ alkyl orunsubstituted C₁-C₈ alkoxy;

R¹ is unsubstituted C₁-C₈ alkyl or a C₁-C₈ alkyl substituted with aperhaloalkyl moiety;

X is OH, substituted or unsubstituted C₁-C₈ alkyl or is taken togetherwith Y and the carbon to which they are attached to form a cyclopropylmoiety;

Y is H, substituted or unsubstituted C₁-C₈ alkyl or is taken togetherwith X and the carbon to which they are attached to form a cyclopropylmoiety; and

R³ is acylamino, carbonylalkoxy, acyloxy, aminoacyl oraminocarbonylalkoxy;

or a salt or solvate thereof.

In one variation, the salt of formula (J-11) is a pharmaceuticallyacceptable salt.

In one variation of formula (J-11), each of Z¹, Z², Z³ and Z⁴ is CR². Inanother variation of formula (J-11), at least one of Z¹, Z², Z³ and Z⁴is N, which may positioned at any of Z¹, Z², Z³ and Z⁴. Where more thanone of Z¹, Z², Z³ and Z⁴ is N, the annular nitrogen atoms may be locatedat any available positions.

In one variation of formula (J-11), R¹ and R² are independently anunsubstituted C₁-C₈ alkyl. In a particular variation of formula (J-11),R¹ and R² are independently an unsubstituted C₁-C₈ alkyl and R³ isacylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. Inone variation, R¹ and R² are each methyl and R³ is acylamino,carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy. In aparticular variation of formula (J-11), R¹ and R² are each methyl and R³is acylamino, carbonylalkoxy, acyloxy, aminoacyl or aminocarbonylalkoxy.

Examples of compounds according to the invention are depicted in Table2A. The compounds depicted may be present as salts even if salts are notdepicted and it is understood that the invention embraces all salts andsolvates of the compounds depicted here, as well as the non-salt andnon-solvate form of the compound, as is well understood by the skilledartisan.

TABLE 2A Representative Compounds Compound Structure J-1

J-2

J-3

J-4

J-5

J-6

J-7

J-8

J-9

J-10

J-11

J-12

J-13

J-14

J-15

J-16

J-17

J-18

J-19

J-20

J-21

J-22

J-23

J-24

J-25

J-26

J-27

J-28

J-29

J-30

Compounds of the formula (K-1) are also detailed herein:

wherein:

R¹, R², R³ and R⁴ are independently H, halo, C₁-C₈ unsubstituted alkylor C₁-C₈ unsubstituted alkoxy, provided that R³ is other than methyl orchloro when R¹, R² and R³ are each H and X is OH and Y is methyl;

R⁵ is unsubstituted C₁-C₈ alkyl or a C₁-C₈ alkyl substituted with aperhaloalkyl moiety;

R⁶ is H or an unsubstituted C₁-C₈ alkyl;

X is OH, C₁-C₈ alkyl or is taken together with Y to form a cyclopropylmoiety;

Y is H, C₁-C₈ alkyl or is taken together with X to form a cyclopropylmoiety,

or a salt thereof, such as a pharmaceutically acceptable salt thereof,or solvate of the foregoing.

In one variation of formula (K-1), R¹ is H, halo or C₁-C₈ unsubstitutedalkoxy; R² is H; R³ is H, halo, C₁-C₈ unsubstituted alkyl or C₁-C₈unsubstituted alkoxy, provided that R³ is other than methyl or chlorowhen R¹, R² and R³ are each H and X is OH and Y is methyl; R⁴ is H orhalo; R⁵ is methyl; R⁶ is H or methyl; X is OH, C₁-C₈ alkyl or is takentogether with Y to form a cyclopropyl moiety and Y is H, C₁-C₈ alkyl oris taken together with X to form a cyclopropyl moiety. In anothervariation of formula (K-1), at least two of R¹, R², R³ and R⁴ are halo(e.g., when R² and R³ are chloro). In another variation of formula(K-1), X is OH and Y is H, methyl, ethyl or isopropyl. In a furthervariation of formula (K-1), R¹, R² and R⁴ are H. In another variation offormula (K-1), three of R¹, R², R³ and R⁴ are H and one is methyl,methoxy, isopropyl, chloro or fluoro.

Also provided are compounds of the formula (K-2):

wherein:

R⁷ is H, hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl, substitutedor unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, thioalkyl, substituted or unsubstituted amino, acylamino,aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl,sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino oracyl; and

Z is H, halo or C₁-C₈ alkyl,

or a salt thereof, such as a pharmaceutically acceptable salt thereof,or solvate of the foregoing.

In one variation of formula (K-2), R⁷ is unsubstituted C₁-C₈ alkyl orhalo. In another variation of formula (K-2), Z is H or halo. In afurther variation of formula (K-2), R⁷ is an unsubstituted C₁-C₈ alkylor halo and Z is H or halo. In a particular variation, R⁷ is methyl orchloro and Z is H, chloro or fluoro.

Compounds of the formula (K-3) are also embraced:

wherein:

R¹, R², R³ and R⁴ are as defined for formula (K-1);

R⁸ is a substituted or unsubstituted aryl or a substituted orunsubstituted heteroaryl; and

X is a C₄-C₆ unsubstituted n-alkyl or cycloalkyl or a C₃-C₆unsubstituted branched alkyl,

or a salt thereof, such as a pharmaceutically acceptable salt thereof,or solvate of the foregoing.

In one variation of formula (K-3), R¹, R² and R⁴ are each H and R³ is anunsubstituted C₁-C₈ alkyl (e.g., methyl) or halo (e.g., chloro). Inanother variation of formula (K-3), X is cyclohexyl, cyclobutyl, n-butylor iso-propyl. In a particular variation of formula (K-3), R¹, R² and R⁴are each H; R³ is an unsubstituted C₁-C₈ alkyl or halo and X iscyclohexyl, cyclobutyl, n-butyl or iso-propyl. In a further variation offormula (K-3), R⁸ is a substituted aryl or an unsubstituted heteroaryl.In one aspect, R⁸ of formula (K-3) is a substituted phenyl or anunsubstituted pyridyl. In a particular aspect, R⁸ of formula (K-3) is4-halo-phenyl or 4-pyridyl. In another variation of formula (K-3), R¹,R² and R⁴ are each H; R³ is an unsubstituted C₁-C₈ alkyl or halo; X iscyclohexyl, cyclobutyl, n-butyl and R⁸ is a substituted phenyl. Inanother variation of formula (K-3), R¹, R² and R⁴ are each H; R³ is anunsubstituted C₁-C₈ alkyl or halo; X is isopropyl and R⁸ is anunsubstituted pyridyl.

Compounds of the formula (K-4) are also provided:

wherein:

R¹, R², R³ and R⁴ are as defined for formula (K-1); and

V is a halo,

or a salt thereof, such as a pharmaceutically acceptable salt thereof,or solvate of the foregoing.

In one variation of formula (K-4), R¹, R² and R⁴ are H and R³ isunsubstituted C₁-C₈ alkyl such as methyl. In another variation offormula (K-4), V is fluoro.

Compounds of the formula (K-5) are also detailed herein:

wherein:

R¹, R² and R⁴ are as defined for formula (K-1); and

R⁸ is 6-pyrimidyl, 3-methyl-4-pyridyl or a phenyl substituted either:(i) with at least one alkoxy or hydroxyl group or (ii) with at least twohalo groups;

R⁹ is an unsubstituted C₁-C₃ alkyl;

or a salt thereof, such as a pharmaceutically acceptable salt thereof,or solvate of the foregoing.

In one variation of formula (K-5), R¹, R² and R⁴ are each H. In anothervariation of formula (K-5), R⁹ is methyl. In a further variation offormula (K-5), R¹, R² and R⁴ are each H and R⁹ is methyl. In anothervariation of formula (K-5), R⁸ is a phenyl substituted with at least oneunsubstituted C₁-C₈ alkoxy group such as methoxy. In one aspect offormula (K-5), R¹, R² and R⁴ are each H and R⁸ is a methoxy-substitutedphenyl. In another aspect of formula (K-5), R⁹ is methyl and R⁸ is amethoxy or hydroxyl-substituted phenyl. In another variation, R⁸ is aphenyl substituted with at least two halo groups and R¹, R² and R⁴ areeach H.

Also provided are compounds of the formula (K-6):

wherein:

R¹, R², R³ and R⁴ are as defined for formula (K-1);

R⁵ is

where T is 3 or 4;

X is H or OH;

Y is H or C₁-C₈ alkyl; and

R⁸ is a substituted or unsubstituted heteroaryl,

or a salt thereof, such as a pharmaceutically acceptable salt thereof,or solvate of the foregoing.

In one variation of formula (K-6), R¹, R² and R⁴ are H. In anothervariation of formula (K-6), R³ is unsubstituted C₁-C₈ alkyl. In anothervariation of formula (K-6), R¹, R² and R⁴ are H and R³ is unsubstitutedC₁-C₈ alkyl. In another variation of formula (K-6), R⁸ is a substitutedor unsubstituted pyridyl. When R⁸ is an unsubstituted pyridyl, it may bebound to the parent structure at any available position, e.g.,4-pyridyl. When R⁸ is a substituted pyridyl, in one aspect the pyridylis substituted with an unsubstituted C₁-C₈ alkyl such as methyl. When R⁸is a substituted pyridyl, it may be bound to the parent structure at anyavailable ring position, e.g., 6-methyl-3-pyridyl. In a particularvariation of formula (K-6), R¹, R² and R⁴ are H; R³ is unsubstitutedC₁-C₈ alkyl and R⁸ is a substituted or unsubstituted pyridyl. In afurther variation of formula (K-6), X and Y are both H. For example, inone aspect a compound is of the formula (K-6) where R¹, R² and R⁴ are H;R³ is unsubstituted C₁-C₈ alkyl and R⁸ is a substituted or unsubstitutedpyridyl and X and Y are both H.

Compounds of the formula (K-7) are also detailed herein:

wherein:

R¹, R² and R⁴ are as defined for formula (K-1);

R³ is methyl or chloro, provided that R³ is methyl when R⁸ is asubstituted heteroaryl;

X is H or OH;

Y is H or C₁-C₈ alkyl; and

R⁸ is a substituted or unsubstituted heteroaryl, or a salt thereof, suchas a pharmaceutically acceptable salt thereof, or solvate of theforegoing.

In one aspect of formula (K-7), R¹, R² and R⁴ are each H. In anotheraspect of formula (K-7), X is H and Y is an unsubstituted C₁-C₈ alkyl.In another aspect of formula (K-7), Y and Y are both H. In a particularvariation of formula (K-7), R¹, R² and R⁴ are each H and either (i) Xand Y are both H or (ii) X is H and Y is an unsubstituted C₁-C₈ alkylsuch as methyl. In a particular variation, R⁸ is a substituted orunsubstituted pyridyl. In a specific variation of formula (K-7), R⁸ is asubstituted or unsubstituted pyridyl and either (i) X and Y are both Hor (ii) X is H and Y is an unsubstituted C₁-C₈ alkyl.

Examples of compounds according to the invention are depicted in Table2B. The compounds depicted may be present as salts even if salts are notdepicted and it is understood that the invention embraces all salts andsolvates of the compounds depicted here, as well as the non-salt andnon-solvate form of the compound, as is well understood by the skilledartisan.

TABEL 2B Representative Compounds According to the Invention. CompoundStructure K-1

K-2

K-3

K-4

K-5

K-6

K-7

K-8

K-9

K-10

K-11

K-12

K-13

K-14

K-15

K-16

K-17

K-18

K-19

K-20

K-21

K-22

K-23

K-24

K-25

K-26

K-27

K-28

K-29

K-30

K-31

K-32

K-33

K-34

K-35

K-36

K-37

K-38

K-39

K-40

K-41

K-42

K-43

K-44

K-45

K-46

K-47

K-48

K-49

K-50

K-51

K-52

K-53

K-54

K-55

K-56

K-57

K-58

K-59

Compounds of the formula (L-1) are also provided:

wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

R² is H, hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl, substitutedor unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, thioalkyl, substituted or unsubstituted amino, acylamino,aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl,sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino oracyl;

X is OH, H, C₁-C₈ unsubstituted alkyl or is taken together with Y toform a cyclic moiety of the formula —OCH₂CH₂O—;

Y is halo, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ alkyl substituted with a carbonylalkoxy,carboxyl or acylamino moiety or is taken together with X to form acyclic moiety of the formula —OCH₂CH₂O—; and

R³ is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl or a substituted or unsubstitutedheterocyclyl;

or a salt or solvate thereof.

In one variation of formula (L-1), R¹ is C₁-C₈ unsubstituted alkyl; R²is C₁-C₈ unsubstituted alkyl, H or halo and R³ is a substituted orunsubstituted aryl or a substituted or unsubstituted heteroaryl. In aparticular variation of formula (L-1), R¹ is methyl, ethyl or isopropyl;R² is methyl, H or chloro and R³ is a substituted or unsubstituted arylor a substituted or unsubstituted heteroaryl. When R³ is anunsubstituted aryl in one variation it is a phenyl moiety. When R³ is asubstituted aryl in one aspect it is a substituted phenyl. When R³ is asubstituted phenyl, the phenyl may be substituted with one or more thanone substituent. For example, on one variation, R³ is a monosubstitutedphenyl where the substituent is a halo group. In another variation, R³is a disubstituted phenyl substituent with two halo groups which may bethe same or different. In a particular variation, R³ is 4-fluorophenyl,2-fluorophenyl, 4-chlorophenyl, 2-chlorophenyl, 4-methoxyphenyl or2,4-difluorophenyl. When R³ is an unsubstituted heteroaryl in onevariation it is a heteroaryl containing an annular nitrogen atom. In oneaspect, when R³ is unsubstituted heteroaryl the heteroaryl contains onlynitrogen and carbon annular atoms. In a particular variation, R³ is anunsubstituted heteroaryl selected from pyridyl or pyrimidinyl andwherein such groups may be bound to the parent structure at anyavailable ring position. For example, in one variation, R³ is 4-pyridyl,3-pyridyl or 6-pyrimidyl. When R³ is a substituted heteroaryl in oneaspect it is a substituted pyridyl. When R³ is a substituted pyridyl,the pyridyl may be substituted with one or more than one substituent andthe substituted pyridyl may be bound to the parent structure at anyavailable ring position. For example, on one variation, R³ is amonosubstituted pyridyl where the substituent is a C₁-C₈unsubstitutedalkyl (e.g., methyl). In a particular variation, R³ is2-methyl-4-pyridyl, 6-methyl-3-pyridyl or 3-methyl-4-pyridyl.

In one variation of formula (L-1), X is OH and Y is an unsubstitutedaryl. In one aspect, Y is phenyl. In another variation, X is H and Y isa C₁-C₈ alkyl substituted with a carbonylalkoxy, carboxyl or acylaminomoiety. In one aspect, Y is a methylene substituted with acarbonylalkoxy, carboxyl or acylamino moiety. In a particular aspect, Yis a moiety selected from the following structures

where R⁴ is a C₁-C₈ unsubstituted alkyl. In one variation, Y is a moietyselected from the following structures

where R⁴ is a C₁-C₈ unsubstituted alkyl and X is H. In anothervariation, X is an unsubstituted C₁-C₈ alkyl and Y is halo. In aparticular aspect, Y is fluoro.

The invention also embraces compounds of the formula (L-2):

or a salt or solvate thereof, where R¹, R² and R³ are as defined forformula (L-1). In one variation of formula (L-2), R¹ and R² areindependently an unsubstituted C₁-C₈ alkyl. In another variation offormula (L-2), R³ is a substituted aryl, such as a substituted phenylgroup, or an unsubstituted heteroaryl, such as pyridyl. In one aspect,R³ is a halo substituted phenyl or pyridyl moiety. When R³ is a halosubstituted phenyl, in a particular variation the phenyl is substitutedwith a fluoro that may be at any position on the phenyl ring. When R³ isa pyridyl group it may be bound to the parent structure at any availablering position. In a particular aspect, R³ is 4-pyridyl. In a particularvariation of formula (L-2), R¹ and R² are independently an unsubstitutedC₁-C₈ alkyl and R³ is a substituted aryl or an unsubstituted heteroaryl.In one variation, R¹ and R² are each methyl and R³ is a substituted arylor unsubstituted heteroaryl. In a particular variation of formula (L-2),R¹ and R² are each methyl and R³ is a fluoro substituted phenyl orpyridyl moiety.

The invention also embraces compounds of the formula (L-3):

or a salt or solvate thereof, where R¹, R² and R³ are as defined forformula (L-1). In one variation of formula (L-3), R¹ is an unsubstitutedC₁-C₈ alkyl (e.g., methyl). In another variation of formula (L-3), R² isH, an unsubstituted C₁-C₈ alkyl (e.g., methyl) or halo (e.g., chloro).In one aspect of formula (L-3), R¹ is an unsubstituted C₁-C₈ alkyl andR² is H, an unsubstituted C₁-C₈ alkyl or halo. In a particular variationof formula (L-3), R¹ is methyl and R² is H, methyl or chloro. In onevariation of formula (L-3), R¹ and R² are independently an unsubstitutedC₁-C₈ alkyl such as methyl. In one variation of formula (L-3), R³ is asubstituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, such as those listed herein for formula (L-1). For example,compounds of the formula (L-3) are intended wherein R³ is anunsubstituted aryl, which in one variation is a phenyl moiety. Compoundsof the formula (L-3) are also intended wherein R³ is a substituted aryl,which in one aspect it is a substituted phenyl. When R³ is a substitutedphenyl, the phenyl may be substituted with one or more than onesubstituent. For example, on one variation, R³ is a monosubstitutedphenyl where the substituent is a halo group. In another variation, R³is a disubstituted phenyl substituent with two halo groups which may bethe same or different. In a particular variation, R³ is 4-fluorophenyl,2-fluorophenyl, 4-chlorophenyl, 2-chlorophenyl, 4-methoxyphenyl or2,4-difluorophenyl. Compounds of formula (L-3) are provided where R³ isan unsubstituted heteroaryl, which in one variation is a heteroarylcontaining an annular nitrogen atom. In one aspect, when R³ isunsubstituted heteroaryl the heteroaryl contains only nitrogen andcarbon annular atoms. In a particular variation of formula (L-3), R³ isan unsubstituted heteroaryl selected from pyridyl or pyrimidinyl andwherein such groups may be bound to the parent structure at anyavailable ring position. For example, in one variation of formula (L-3),R³ is 4-pyridyl, 3-pyridyl or 6-pyrimidyl. When R³ is a substitutedheteroaryl in one aspect it is a substituted pyridyl. When R³ is asubstituted pyridyl, the pyridyl may be substituted with one or morethan one substituent and the substituted pyridyl may be bound to theparent structure at any available ring position. For example, in onevariation of formula (L-3), R³ is a monosubstituted pyridyl where thesubstituent is a C₁-C₈unsubstituted alkyl (e.g., methyl). In aparticular variation of formula (L-3), R³ is 2-methyl-4-pyridyl,6-methyl-3-pyridyl or 3-methyl-4-pyridyl. In another variation offormula (L-3), R³ is a substituted aryl, such as a substituted phenylgroup. In one aspect, R³ is a halo substituted phenyl. When R³ is a halosubstituted phenyl, in a particular variation the phenyl is substitutedwith a fluoro or chloro that may be at any position on the phenyl ring.In a further variation of formula (L-3), R¹ is an unsubstituted C₁-C₈alkyl; R² is H, an unsubstituted C₁-C₈ alkyl or halo and R³ is asubstituted or unsubstituted phenyl, a substituted or unsubstitutedpyridyl or an unsubstituted pyrimidyl. In a particular variation,compounds of formula (L-3) are provided where R¹ is methyl, R² is H,methyl or chloro and R³ is a substituted or unsubstituted phenyl, asubstituted or unsubstituted pyridyl or an unsubstituted pyrimidyl.

Compounds of the formula (L-4) are also provided:

or a salt or solvate thereof, where R¹, R² and R³ are as detailed forformula (L-1) and R⁴ is an unsubstituted C₁-C₈ alkyl. In one variationof formula (L-4), R¹ is an unsubstituted C₁-C₈ alkyl. In one variationof formula (L-4), R₂ is an unsubstituted C₁-C₈ alkyl or halo. In onevariation of formula (L-4), R¹ and R² are independently an unsubstitutedC₁-C₈ alkyl (e.g., methyl or ethyl). In one variation of formula (L-4),R¹ is an unsubstituted C₁-C₈ alkyl (e.g., methyl or ethyl) and R² is anunsubstituted C₁-C₈ alkyl or halo. In a particular variation of formula(L-4), R⁴ is a C₁-C₄ unsubstituted alkyl. In a further variation offormula (L-4), R⁴ is methyl, ethyl, propyl or butyl. In one aspect, R⁴is iso-propyl. In another aspect, R⁴ is tert-butyl. In a particularvariation of formula (L-4), R¹ is an unsubstituted C₁-C₈ alkyl; R² is anunsubstituted C₁-C₈ alkyl or halo and R⁴ is a C₁-C₄ unsubstituted alkyl.In another variation of formula (L-4), R³ is a substituted orunsubstituted aryl or a substituted or unsubstituted heteroaryl, such asthose listed herein for formula (L-1). For example, compounds of theformula (L-4) are intended wherein R³ is a substituted aryl, which inone aspect it is a substituted phenyl. When R³ is a substituted phenyl,the phenyl may be substituted with one or more than one substituent. Forexample, on one variation, R³ is a monosubstituted phenyl where thesubstituent is a halo group. In another variation, R³ is adihalosubstituted phenyl wherein the halo moieties may be the same ordifferent. In a particular variation, R³ is 4-fluorophenyl,4-chlorophenyl, 2,4-difluorophenyl or 4-methoxyphenyl. Compounds offormula (L-4) are also provided where R³ is an unsubstituted heteroaryl,which in one variation is a heteroaryl containing an annular nitrogenatom. In one aspect, when R³ is unsubstituted heteroaryl the heteroarylcontains only nitrogen and carbon annular atoms. In a particularvariation of formula (L-4), R³ is an unsubstituted heteroaryl selectedfrom pyridyl or pyrimidinyl and wherein such groups may be bound to theparent structure at any available ring position. For example, in onevariation of formula (L-4), R³ is 4-pyridyl, 3-pyridyl or 6-pyrimidyl.When R³ is a substituted heteroaryl in one aspect it is a substitutedpyridyl. When R³ is a substituted pyridyl, the pyridyl may besubstituted with one or more than one substituent and the substitutedpyridyl may be bound to the parent structure at any available ringposition. For example, in one variation of formula (L-4), R³ is amonosubstituted pyridyl where the substituent is a C₁-C₈unsubstitutedalkyl (e.g., methyl). In a particular variation of formula (L-4), R³ is2-methyl-4-pyridyl, 6-methyl-3-pyridyl or 3-methyl-4-pyridyl. In afurther variation of formula (L-4), R¹ is an unsubstituted C₁-C₈ alkyl;R² is an unsubstituted C₁-C₈ alkyl or halo; R⁴ is a C₁-C₄ unsubstitutedalkyl and R³ is a substituted phenyl, a substituted or unsubstitutedpyridyl or an unsubstituted pyrimidyl. In a particular variation,compounds of formula (L-4) are provided where R¹ is methyl or ethyl, R²is methyl or chloro; R⁴ is methyl, ethyl, isopropyl or tert-butyl and R³is a substituted phenyl, a substituted or unsubstituted pyridyl or anunsubstituted pyrimidyl.

Also provided herein are compounds of the formula (L-5):

or a salt of solvate thereof, where R¹, R² and R³ are as detailed forformula (L-1). In one variation of formula (L-5), R¹ is an unsubstitutedC₁-C₈ alkyl (e.g., methyl). In another variation of formula (L-5), R² isunsubstituted C₁-C₈ alkyl (e.g., methyl) or halo (e.g., chloro). In aparticular variation of formula (L-5), R¹ is an unsubstituted C₁-C₈alkyl and R² is unsubstituted C₁-C₈ alkyl or halo. In another variationof formula (L-5), R¹ and R² are independently an unsubstituted C₁-C₈alkyl (e.g., methyl). In one variation of formula (L-5), R³ is asubstituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, such as those listed herein for formula (L-1). For example,compounds of the formula (L-5) are intended wherein R³ is a substitutedaryl, which in one aspect it is a substituted phenyl. When R³ is asubstituted phenyl, the phenyl may be substituted with one or more thanone substituent. For example, on one variation, R³ is a monosubstitutedphenyl where the substituent is a halo group. In another variation, R³is a disubstituted phenyl substituent with two halo groups which may bethe same or different. In a particular variation, R³ is 4-fluorophenyl,2-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl or 2,4-difluorophenyl.Compounds of formula (L-5) are also provided where R³ is anunsubstituted heteroaryl, which in one variation is a heteroarylcontaining an annular nitrogen atom. In one aspect, when R³ isunsubstituted heteroaryl the heteroaryl contains only nitrogen andcarbon annular atoms. In a particular variation of formula (L-5), R³ isan unsubstituted heteroaryl selected from pyridyl or pyrimidinyl andwherein such groups may be bound to the parent structure at anyavailable ring position. For example, in one variation of formula (L-5),R³ is 4-pyridyl, 3-pyridyl or 6-pyrimidyl. When R³ is a substitutedheteroaryl in one aspect it is a substituted pyridyl. When R³ is asubstituted pyridyl, the pyridyl may be substituted with one or morethan one substituent and the substituted pyridyl may be bound to theparent structure at any available ring position. For example, in onevariation of formula (L-5), R³ is a monosubstituted pyridyl where thesubstituent is a C₁-C₈unsubstituted alkyl (e.g., methyl). In aparticular variation of formula (L-5), R³ is 2-methyl-4-pyridyl,6-methyl-3-pyridyl or 3-methyl-4-pyridyl. In one variation of formula(L-5), R¹ is an unsubstituted C₁-C₈ alkyl, R² is unsubstituted C₁-C₈alkyl or halo and R³ is a substituted phenyl, a substituted orunsubstituted pyridyl or an unsubstituted pyrimidyl. In a particularvariation of formula (L-5), R¹ and R² are independently an unsubstitutedC₁-C₈ alkyl and R³ is a substituted phenyl, a substituted orunsubstituted pyridyl or an unsubstituted pyrimidyl.

Additional compounds detailed herein are of the formula (L-6):

or a salt of solvate thereof, where R¹, R² and R³ are as detailed forformula (L-1). In one variation of formula (L-6), R¹ is an unsubstitutedC₁-C₈ alkyl (e.g., methyl or ethyl). In another variation of formula(L-6), R² is unsubstituted C₁-C₈ alkyl (e.g., methyl) or halo (e.g.,chloro). In a particular variation of formula (L-6), R¹ is anunsubstituted C₁-C₈ alkyl and R² is unsubstituted C₁-C₈ alkyl or halo.In another variation of formula (L-6), R¹ and R² are independently anunsubstituted C₁-C₈ alkyl. In one variation of formula (L-6), R³ is asubstituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, such as those listed herein for formula (L-1). For example,compounds of the formula (L-6) are intended wherein R³ is a substitutedaryl, which in one aspect it is a substituted phenyl. When R³ is asubstituted phenyl, the phenyl may be substituted with one or more thanone substituent. For example, on one variation, R³ is a monosubstitutedphenyl where the substituent is a halo group. In another variation, R³is a disubstituted phenyl substituent with two halo groups which may bethe same or different. In a particular variation, R³ is 4-fluorophenyl,2-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl or 2,4-difluorophenyl.Compounds of formula (L-6) are also provided where R³ is anunsubstituted heteroaryl, which in one variation is a heteroarylcontaining an annular nitrogen atom. In one aspect, when R³ isunsubstituted heteroaryl the heteroaryl contains only nitrogen andcarbon annular atoms. In a particular variation of formula (L-6), R³ isan unsubstituted heteroaryl selected from pyridyl or pyrimidinyl andwherein such groups may be bound to the parent structure at anyavailable ring position. For example, in one variation of formula (L-6),R³ is 4-pyridyl, 3-pyridyl or 6-pyrimidyl. When R³ is a substitutedheteroaryl in one aspect it is a substituted pyridyl. When R³ is asubstituted pyridyl, the pyridyl may be substituted with one or morethan one substituent and the substituted pyridyl may be bound to theparent structure at any available ring position. For example, in onevariation of formula (L-6), R³ is a monosubstituted pyridyl where thesubstituent is a C₁-C₈unsubstituted alkyl (e.g., methyl). In aparticular variation of formula (L-6), R³ is 2-methyl-4-pyridyl,6-methyl-3-pyridyl or 3-methyl-4-pyridyl. In one variation of formula(L-6), R¹ is an unsubstituted C₁-C₈ alkyl, R² is unsubstituted C₁-C₈alkyl or halo and R³ is a substituted phenyl, a substituted or pyridylor an unsubstituted pyrimidyl.

Compounds of the formula (L-7) are also detailed herein:

or a salt or solvate thereof, where R¹, R² and R³ are as defined forformula (L-1). In one variation of formula (L-7), R¹ is an unsubstitutedC₁-C₈ alkyl (e.g., methyl, ethyl or isopropyl). In another variation offormula (L-7), R² is unsubstituted C₁-C₈ alkyl (e.g., methyl) or halo(e.g., chloro). In a particular variation of formula (L-7), R¹ is anunsubstituted C₁-C₈ alkyl and R² is unsubstituted C₁-C₈ alkyl or halo.In another variation of formula (L-7), R¹ and R² are independently anunsubstituted C₁-C₈ alkyl. In one variation of formula (L-7), R³ is asubstituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, such as those listed herein for formula (L-1). For example,compounds of the formula (L-7) are intended wherein R³ is a substitutedaryl, which in one aspect it is a substituted phenyl. When R³ is asubstituted phenyl, the phenyl may be substituted with one or more thanone substituent. For example, on one variation, R³ is a monosubstitutedphenyl where the substituent is a halo group. In another variation, R³is a disubstituted phenyl substituent with two halo groups which may bethe same or different. In a particular variation, R³ is 4-fluorophenyl,4-chlorophenyl, 4-methoxyphenyl or 2,4-difluorophenyl. Compounds offormula (L-7) are also provided where R³ is an unsubstituted heteroaryl,which in one variation is a heteroaryl containing an annular nitrogenatom. In one aspect, when R³ is unsubstituted heteroaryl the heteroarylcontains only nitrogen and carbon annular atoms. In a particularvariation of formula (L-7), R³ is an unsubstituted heteroaryl selectedfrom pyridyl or pyrimidinyl and wherein such groups may be bound to theparent structure at any available ring position. For example, in onevariation of formula (L-7), R³ is 4-pyridyl, 3-pyridyl or 6-pyrimidyl.When R³ is a substituted heteroaryl in one aspect it is a substitutedpyridyl. When R³ is a substituted pyridyl, the pyridyl may besubstituted with one or more than one substituent and the substitutedpyridyl may be bound to the parent structure at any available ringposition. For example, in one variation of formula (L-7), R³ is amonosubstituted pyridyl where the substituent is a C₁-C₈unsubstitutedalkyl (e.g., methyl). In a particular variation of formula (L-7), R³ is6-methyl-3-pyridyl or 3-methyl-4-pyridyl. In one variation of formula(L-7), R¹ is an unsubstituted C₁-C₈ alkyl, R² is unsubstituted C₁-C₈alkyl or halo and R³ is a substituted phenyl, a substituted or pyridylor an unsubstituted pyrimidyl.

Compounds of the formula (L-8) are also provided:

or a salt or solvate thereof, where R¹, R² and R³ are as defined forformula (L-1). In one variation of formula (L-8), R¹ and R² are each aC₁-C₈ unsubstituted alkyl group. In another variation of formula (L-8),R³ is an unsubstituted heteroaryl such as pyridyl. In a particularvariation of formula (L-8), R¹ and R² are each a C₁-C₈ unsubstitutedalkyl group and R³ is an unsubstituted heteroaryl.

Examples of compounds according to the invention are depicted in Table2C. The compounds depicted may be present as salts even if salts are notdepicted and it is understood that the invention embraces all salts andsolvates of the compounds depicted here, as well as the non-salt andnon-solvate form of the compound, as is well understood by the skilledartisan.

TABLE 2C Representative Compounds According to the Invention. CompoundStructure L-1

L-2

L-3

L-4

L-5

L-6

L-7

L-8

L-9

L-10

L-11

L-12

L-13

L-14

L-15

L-16

L-17

L-18

L-19

L-20

L-21

L-22

L-23

L-24

L-25

L-26

L-27

L-28

L-29

L-30

L-31

L-32

L-33

L-34

L-35

L-36

L-37

L-38

L-39

L-40

L-41

L-42

L-43

L-44

L-45

L-46

L-47

L-48

L-49

L-50

L-51

L-52

L-53

L-54

L-55

L-56

L-57

L-58

L-59

L-60

L-61

Pharmaceutical compositions of any of the compounds detailed herein areembraced by this invention. Thus, the invention includes pharmaceuticalcompositions comprising a compound of the invention or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or excipient. In one aspect, the pharmaceuticallyacceptable salt is an acid addition salt, such as a salt formed with aninorganic or organic acid. Pharmaceutical compositions according to theinvention may take a form suitable for oral, buccal, parenteral, nasal,topical or rectal administration, or a form suitable for administrationby inhalation.

A compound as detailed herein may in one aspect be in a purified formand compositions comprising a compound in purified forms are detailedherein. Compositions comprising a compound as detailed herein or a saltthereof are provided, such as compositions of substantially purecompounds. In some embodiments, a composition containing a compound asdetailed herein or a salt thereof is in substantially pure form. Unlessotherwise stated, “substantially pure” intends a composition thatcontains no more than 35% impurity, wherein the impurity denotes acompound other than the compound comprising the majority of thecomposition or a salt thereof. Taking compound 1 as an example, acomposition of substantially pure compound 1 intends a composition thatcontains no more than 35% impurity, wherein the impurity denotes acompound other than compound 1 or a salt thereof. In one variation, acomposition of substantially pure compound or a salt thereof is providedwherein the composition contains no more than 25% impurity. In anothervariation, a composition of substantially pure compound or a saltthereof is provided wherein the composition contains or no more than 20%impurity. In still another variation, a composition of substantiallypure compound or a salt thereof is provided wherein the compositioncontains or no more than 10% impurity. In a further variation, acomposition of substantially pure compound or a salt thereof is providedwherein the composition contains or no more than 5% impurity. In anothervariation, a composition of substantially pure compound or a saltthereof is provided wherein the composition contains or no more than 3%impurity. In still another variation, a composition of substantiallypure compound or a salt thereof is provided wherein the compositioncontains or no more than 1% impurity. In a further variation, acomposition of substantially pure compound or a salt thereof is providedwherein the composition contains or no more than 0.5% impurity.

In one variation, compounds of the invention are synthetic compoundsprepared for administration to an individual. In another variation,compositions are provided containing compounds of the invention insubstantially pure form. In another variation, the invention embracespharmaceutical compositions comprising a compound of the invention and apharmaceutically acceptable carrier. In another variation, methods ofadministering a compound of the invention are provided. The purifiedforms, pharmaceutical compositions and methods of administering thecompounds are suitable for any compound or form thereof detailed herein,such as compound 11.

Strikingly, it has been discovered that compounds included in theinvention that contain a substituted vinyl moiety, such as methylvinyl,exhibit a lower binding affinity to H₁ as compared to theirunsubstituted vinyl counterparts. Thus, it is believed that substitutedvinyl moieties, such as methylvinyl, may be responsible for reduced H₁affinity.

Compounds that exhibit affinity for the histamine receptor H₁ may induceundesirable side effects, such as metabolic syndrome, diabetes type 2,weight gain, hyperlipidemia, hyperglycemia, hypertension and drowsiness(Kroeze et al., Neuropsychopharmacology (2003) 28, 519-526). The numberand extent of undesirable side effects increases with increasingaffinity for the H₁ receptor. Thus, in one aspect, compounds of theformulae herein display reduced, low or no affinity to histaminereceptor H₁. Compounds with low affinity to H₁ are those compounds whichdisplay less than about 80% inhibition of binding of a ligand to H₁.Inhibition of binding of a ligand to H₁ for all variations detailedherein is determined by a suitable assay known in the art such as theassay described herein. In some variations, compounds of the formulaeherein inhibit binding of a ligand to H₁ by less than about any of 80%,75%, 70%, 65%, 60% 55% and 50%. In one variation, compounds of theformulae herein inhibit binding of a ligand to H₁ by between about 50%to about 80%. In aspect, compounds of the formulae herein inhibitbinding of a ligand to H₁ by less than about any of 80%, 75%, 70%, 65%,60% 55% and 50% at any concentration, such as those detailed herein,e.g., 0.1 μM and 1 μM. In one variation, compounds of the formulaeherein inhibit binding of Pyrilamine to H₁ as determined in the assaydescribed herein. In a further variation, percent inhibition of bindingto H₁ is measured by assays detailed herein.

Compounds containing a substituted vinyl moiety, such as methylvinylmoiety, are detailed herein wherein the compounds exhibit reduced H₁affinity as compared to their unsubstituted vinyl counterparts. In oneaspect, compounds that contain a substituted vinyl moiety, such as amethylvinyl moiety, exhibit low or no H₁ affinity and thus providecompounds with fewer or lesser undesirable side effects than compoundscontaining an unsubstituted vinyl moiety. In one variation, compounds asdetailed herein containing a substituted vinyl moiety, such asmethylvinyl, inhibit binding of a ligand to H₁ by less than about any of80%, 75%, 70%, 65%, 60% 55% and 50%. In another variation, compounds asdetailed herein containing a substituted vinyl moiety, such asmethylvinyl, inhibit binding of a ligand to H₁ by less than about any of50%, 40%, 30%, 20%, 10% and 5%.

General Description of Biological Assays

The binding properties of compounds disclosed herein to a panel ofaminergic G protein-coupled receptors including adrenergic receptors,dopamine receptors, serotonin receptors, histamine receptors and animidazoline receptor may be determined. Binding properties may beassessed by methods known in the art, such as competitive bindingassays. In one variation, compounds are assessed by the binding assaysdetailed herein. Compounds disclosed herein may also be tested incell-based assays or in in vivo models for further characterization. Inone aspect, compounds disclosed herein are of any formula detailedherein and further display one or more of the following characteristics:inhibition of binding of a ligand to an adrenergic receptor (e.g.,α_(1D), α_(2A) and α_(2B)), inhibition of binding of a ligand to aserotonin receptor (e.g., 5-HT_(2A), 5-HT_(2C), 5-HT₆ and 5-HT₇),inhibition of binding of a ligand to a dopamine receptor (e.g., D_(2L)),and inhibition of binding of a ligand to a histamine receptor (e.g., H₁,H₂ and H₃); agonist/antagonist activity to a serotonin receptor (e.g.,5-HT_(2A), 5-HT₆); agonist/antagonist activity to a dopamine receptor(e.g., D_(2L), D_(2S)); agonist/antagonist activity to a histaminereceptor (e.g., H₁); activity in a neurite outgrowth assay; efficacy ina preclinical model of memory dysfunction associated with cholinergicdysfunction/hypofunction; efficacy in a preclinical model of attentionimpulsivity and executive function, and efficacy in a preclinical modelof schizophrenia.

In one variation, inhibition of binding of a ligand to a receptor ismeasured in the assays described herein. In another variation,inhibition of binding of a ligand is measured in an assay known in theart. In one variation, binding of a ligand to a receptor is inhibited byat least about 80% as determined in a suitable assay known in the artsuch as the assays described herein. In one variation, binding of aligand to a receptor is inhibited by greater than about any one of 80%,85%, 90%, 95%, 100%, or between about 85% and about 95% or between about90% and about 100% as determined in a suitable assay known in the artsuch as the assays described herein. In one variation, binding of aligand to a receptor is inhibited by at least about 80%±20% asdetermined in an assay known in the art.

In one variation, a compound of the invention inhibits binding of aligand to at least one receptor and as many as eleven as detailed herein(e.g. α_(1D), α_(2A), α_(2B), 5-HT_(2A), 5-HT_(2C), 5-HT₆, 5-HT₇, D₂,H₁, H₂, H₃). In one variation, a compound of the invention inhibitsbinding of a ligand to at least one receptor and as many as eleven asdetailed herein (e.g. α_(1D), α_(2A), α_(2B), 5-HT_(2A), 5-HT_(2C),5-T₆, 5-HT₇, D_(2L), H₁, H₂, H₃). In one variation, a compound of theinvention inhibits binding of a ligand to at least one and as many aseleven receptors detailed herein and further displays agonist orantagonist activity to one or more receptors detailed herein (e.g.,serotonin receptor 5-HT_(2A), serotonin receptor 5-HT₆, dopaminereceptor D_(2L), and dopamine receptor D_(2S) and histamine receptor H₁)as measured in the assays described herein. In one variation, agonistresponse of serotonin receptor 5-HT_(2A) is inhibited by compounds ofthe invention by at least about any one of 50%, 50%, 70%, 80%, 90%,100%, 110%, 120%, 130%, 140%, 150% as determined in a suitable assaysuch as the assay described herein.

In one variation, a compound of the invention displays the abovedescribed neurotransmitter receptor binding profile i.e. inhibitsbinding of a ligand to at least one receptor and as many as eleven asdetailed herein and further stimulates neurite outgrowth, e.g. asmeasured by the assays described herein. Certain compounds of theinvention showed activity in neurite outgrowth assays using primaryneurons in culture. Data is presented indicating that a compound of theinvention has activity comparable in magnitude to that of naturallyoccurring prototypical neurotrophic proteins such as brain derivedneurotrophic factor (BDNF) and nerve growth factor (NGF). Notably,neurite outgrowth plays a critical part of new synaptogenesis, which isbeneficial for the treatment of neuronal disorders. In one variation,neuronal disorders include ADHD. In one variation, neurite outgrowth isobserved with a potency of about 1 μM as measured in a suitable assayknown in the art such as the assays described herein. In anothervariation, neurite outgrowth is observed with a potency of about 500 nM.In a further variation, neurite outgrowth is observed with a potency ofabout 50 nM. In another variation, neurite outgrowth is observed with apotency of about 5 nM.

In another variation, a compound of the invention inhibits binding of aligand to at least one receptor and as many as eleven as detailedherein, further displays agonist or antagonist activity to one or morereceptors detailed herein and further stimulates neurite outgrowth.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors as detailedherein and/or display the above described neurotransmitter receptorbinding profile and further shows efficacy in a preclinical model ofmemory dysfunction associated with cholinergic dysfunction/hypofunction,and in preclinical models of attention impulsivity and executivefunction, i.e. shows pro-cognitive effects in a preclinical model ofmemory dysfunction. Compounds of the invention have been shown to beeffective in a preclinical model of memory dysfunction associated withcholinergic hypofunction. As H1 antagonism may contribute to sedation,weight gain and reduced cognition, low affinity (less than about 80%inhibition of binding of Pyrilamine at 1 μM in the assay describedherein) for this receptor may be associated with pro-cognitive effectsand a more desirable side effect profile. Furthermore, compounds of theinvention with increased potency as a 5-HT₆ antagonist may havecognition-enhancing effects as serotonin acting through this receptormay impair memory.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors as detailedherein, further shows efficacy in a preclinical model of memorydysfunction associated with cholinergic dysfunction/hypofunction i.e.shows pro-cognitive effects in a preclinical model of memorydysfunction, in preclinical models of attention impulsivity andexecutive function, and further displays agonist or antagonist activityto one or more receptors detailed herein.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors as detailedherein, further shows efficacy in a preclinical model of memorydysfunction associated with cholinergic dysfunction/hypofunction i.e.shows pro-cognitive effects in a preclinical model of memorydysfunction, in preclinical models of attention impulsivity andexecutive function, and further stimulates neurite outgrowth.

In another variation, a compound of the invention inhibits at least oneand as many as eleven receptors as detailed herein, further showsefficacy in a preclinical model of memory dysfunction associated withcholinergic dysfunction/hypofunction i.e. shows pro-cognitive effects ina preclinical model of memory dysfunction, in preclinical models ofattention impulsivity and executive function, and further displaysagonist or antagonist activity to one or more receptor detailed hereinand further stimulates neurite outgrowth.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors and furtherpossesses anti-psychotic effects as measured in a preclinical model ofschizophrenia, i.e., shows efficacy in a preclinical model ofschizophrenia.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia and further displaysagonist or antagonist activity to one or more receptors detailed herein.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia and further stimulatesneurite outgrowth.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of memory dysfunction associated withcholinergic dysfunction/hypofunction such as enhancement of memoryretention and reduction of memory impairment, in preclinical models ofattention impulsivity and executive function, and further shows efficacyin a preclinical model of schizophrenia.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia, further displaysagonist or antagonist activity to one or more receptors detailed hereinand further shows efficacy in a preclinical model of memory dysfunctionassociated with cholinergic dysfunction/hypofunction such as enhancementof memory retention and reduction of memory impairment, and inpreclinical models of attention impulsivity and executive function.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia, further stimulatesneurite outgrowth and further shows efficacy in a preclinical model ofmemory dysfunction associated with cholinergic dysfunction/hypofunctionsuch as enhancement of memory retention and reduction of memoryimpairment, and in preclinical models of attention impulsivity andexecutive function.

In a further variation, a compound of the invention inhibits binding toat least one and as many as eleven receptors detailed herein, furtherdisplays agonist or antagonist activity to one or more receptorsdetailed herein, further stimulates neurite outgrowth and further showsefficacy in a preclinical model of schizophrenia.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia, further displaysagonist or antagonist activity to one or more receptors detailed herein,further stimulates neurite outgrowth and further shows efficacy in apreclinical model of memory dysfunction associated with cholinergicdysfunction/hypofunction such as enhancement of memory retention andreduction of memory impairment, and in preclinical models of attentionimpulsivity and executive function.

In another variation, a compound of the invention stimulates neuriteoutgrowth. In another variation, a compound of the invention showsefficacy in a preclinical model of schizophrenia and further stimulatesneurite outgrowth. In another variation, a compound of the inventionstimulates neurite outgrowth and further shows efficacy in a preclinicalmodel of memory dysfunction associated with cholinergicdysfunction/hypofunction such as enhancement of memory retention andreduction of memory impairment, and in preclinical models of attentionimpulsivity and executive function. In another variation, a compound ofthe invention shows efficacy in a preclinical model of schizophrenia,further stimulates neurite outgrowth and further shows efficacy in apreclinical model of memory dysfunction associated with cholinergicdysfunction/hypofunction such as enhancement of memory retention andreduction of memory impairment, and in preclinical models of attentionimpulsivity and executive function.

In one aspect, compounds of the invention inhibit binding of a ligand toadrenergic receptors α_(1D), α_(2A), αα_(2B) and inhibit binding of aligand to serotonin receptor 5-HT₆. In another variation, compounds ofthe invention inhibit binding of a ligand to adrenergic receptorsα_(1D), αα_(2A), α_(2B), to serotonin receptor 5-HT₆ and to any one ormore of the following receptors: serotonin receptor 5-HT₇, 5-HT_(2A) and5-HT_(2C). In another variation, compounds of the invention inhibitbinding of a ligand to adrenergic receptors α_(1D), α_(2A), α_(2B), toserotonin receptor 5-HT₆ and to any one or more of the followingreceptors: serotonin receptor 5-HT₇, 5-HT_(2A) and 5-HT_(2C) and furthershow weak inhibition of binding of a ligand to histamine receptor H₁and/or H₂. In one variation, compounds of the invention that alsodisplay strong inhibition of binding of a ligand to the serotoninreceptor 5-HT₇ are particularly desired. In another variation, compoundsof the invention inhibit binding of a ligand to adrenergic receptorsα_(1D), α_(2A), α_(2B), to serotonin receptor 5-HT₆ and further showweak inhibition of binding of a ligand to histamine receptor H₁ and/orH₂. Weak inhibition of binding of a ligand to the histamine H₁ receptoris permitted as agonists of this receptor have been implicated instimulating memory as well as weight gain. In one variation, binding tohistamine receptor H1 is inhibited by less than about 80%. In anothervariation, binding of a ligand to histamine receptor H1 is inhibited byless than about any of 75%, 70%, 65%, 60%, 55%, or 50% as determined bya suitable assay known in the art such as the assays described herein.

In another variation, compounds of the invention inhibit binding of aligand to dopamine receptor D₂. In another variation, compounds of theinvention inhibit binding of a ligand to dopamine receptor D₂ and toserotonin receptor 5-HT_(2A). In another variation, compounds of theinvention inhibit binding of a ligand to dopamine receptor D_(2L). Inanother variation, compounds of the invention inhibit binding of aligand to dopamine receptor D_(2L) and to serotonin receptor 5-HT_(2A).

In another variation, compounds of the invention inhibit binding of aligand to histamine receptor H₁. In certain aspects, compounds of theinvention further show one or more of the following properties: stronginhibition of binding of a ligand to the serotonin 5-HT₇ receptor,strong inhibition of binding of a ligand to the serotonin 5-HT_(2A)receptor, strong inhibition of binding of a ligand to the serotonin5-HT_(2C) receptor, weak inhibition of binding of a ligand to thehistamine H₁ receptor, weak inhibition of binding of ligands to thehistamine H₂ receptor, and antagonist activity to serotonin receptor5-HT_(2A).

In one variation, compounds of the invention show any of the receptorbinding aspects detailed herein and further display agonist/antagonistactivity to one or more of the following receptors: serotonin receptor5-HT_(2A), serotonin receptor 5-HT₆, dopamine receptor D_(2L), dopaminereceptor D_(2S) and histamine receptor H₁. In one variation, compoundsof the invention show any of the receptor binding aspects detailedherein and further stimulate neurite outgrowth. In one variation,compounds of the invention show any of the receptor binding aspectsdetailed herein and further show efficacy in a preclinical model ofmemory dysfunction associated with cholinergic dysfunction/hypofunction,such as enhancement of memory retainment and reduction of memoryimpairment, and in preclinical models of attention impulsivity andexecutive function. In one variation, compounds of the invention showany of the receptor binding aspects detailed herein and further showefficacy in a preclinical model of schizophrenia. In one variation,compounds of the invention show any of the receptor binding aspectsdetailed herein and further show efficacy in any one or more ofagonist/antagonist assays (e.g., to serotonin receptor 5-HT_(2A), 5-HT₆,dopamine receptor D_(2L), dopamine receptor D_(2S) and histaminereceptor H₁), neurite outgrowth, a preclinical model of memorydysfunction associated with cholinergic dysfunction/hypofunction and apreclinical model of schizophrenia.

In some aspects, compounds of the invention inhibit binding of a ligandto adrenergic receptors α_(1D), α_(2A), α_(2B), serotonin receptor 5-HT₆and dopamine receptor D₂ by at least about 80% as determined in asuitable assay known in the art such as the assays described herein. Inone variation binding is inhibited by at least about 80% as measured ina suitable assay such as the assays described herein. In some aspects,compounds of the invention inhibit binding of a ligand to adrenergicreceptors α_(1D), α_(2A), α_(2B), serotonin receptor 5-HT₆ and dopaminereceptor D_(2L) by at least about 80% as determined in a suitable assayknown in the art such as the assays described herein. In one variationbinding is inhibited by at least about 80% as measured in a suitableassay such as the assays described herein. In one variation, binding ofa ligand to a receptor is inhibited by greater than about any one of80%, 85%, 90%, 95%, 100%, or between about 85% and about 95%, or betweenabout 90% and about 100% as determined in a suitable assay known in theart such as the assays described herein.

In some aspects, compounds of the invention display the above describedneurotransmitter receptor binding profile and further show antipsychoticeffects. It is recognized that compounds of the invention have bindingprofiles similar to compounds with antipsychotic activity and severalcompounds of the invention have been shown to be effective in apreclinical model of schizophrenia. In addition, compounds of theinvention might possess the cognitive enhancing properties of dimebonand thus add to the beneficial pharmacology profile of theseantipsychotic molecules. In one variation, compounds of the inventiondisplay the above described neurotransmitter receptor binding profileand further show pro-cognitive effects in a preclinical model of memorydysfunction such as enhancement of memory retention and reduction ofmemory impairment. In another variation, compounds of the inventiondisplay the above described neurotransmitter receptor binding profileand do not show pro-cognitive effects in a preclinical model of memorydysfunction, learning and memory.

In one variation, compounds of the invention demonstrate pro-cognitiveeffects in a preclinical model of memory dysfunction, learning andmemory. In a further variation, compounds of the invention possessanti-psychotic effects in a preclinical model of schizophrenia. In afurther variation, compounds of the invention demonstrate pro-cognitiveeffects in a preclinical model of memory dysfunction, learning andmemory and further possess anti-psychotic effects in a preclinical modelof schizophrenia.

Overview of the Methods

The compounds described herein may be used to treat, prevent, delay theonset and/or delay the development of cognitive disorders, psychoticdisorders, neurotransmitter-mediated disorders and/or neuronal disordersin individuals, such as humans. In one aspect, the compounds describedherein may be used to treat, prevent, delay the onset and/or delay thedevelopment of a cognitive disorder. In one aspect, cognitive disordersinclude ADHD. In one variation, cognitive disorder as used hereinincludes and intends disorders that contain a cognitive component, suchas psychotic disorders (e.g., schizophrenia) containing a cognitivecomponent (e.g., CIAS). In another aspect, the compounds describedherein may be used to treat, prevent, delay the onset and/or delay thedevelopment of a psychotic disorder. In one variation, psychoticdisorder as used herein includes and intends disorders that contain apsychotic component, for example cognitive disorders (e.g., Alzheimer'sdisease) that contain a psychotic component (e.g., psychosis ofAlzheimer's Disease or dementia). In one variation, methods of improvingat least one cognitive and/or psychotic symptom associated withschizophrenia are provided. In one aspect, methods of improvingcognition in an individual who has or is suspected of having CIAS areprovided. In a particular aspect, methods of treating schizophrenia areprovided wherein the treatment provides for an improvement in one ormore negative symptom and/or one or more positive symptom and/or one ormore disorganized symptom of schizophrenia. In yet another aspect, thecompounds described herein may be used to treat, prevent, delay theonset and/or delay the development of a neurotransmitter-mediateddisorders disorder. In one aspect, neurotransmitter-mediated disordersinclude ADHD. In one embodiment, the neurotransmitter-mediated disorderincludes spinal cord injury, diabetic neuropathy, allergic diseases(including food allergies) and diseases involving geroprotectiveactivity such as age-associated hair loss (alopecia), age-associatedweight loss and age-associated vision disturbances (cataracts). Inanother variation, the neurotransmitter-mediated disorder includesspinal cord injury, diabetic neuropathy, fibromyalgia and allergicdiseases (including food allergies). In still another embodiment, theneurotransmitter-mediated disorder includes Alzheimer's disease,Parkinson's Disease, autism, ADD, ADHD, Guillain-Barré syndrome, mildcognitive impairment, multiple sclerosis, stroke and traumatic braininjury. In yet another embodiment, the neurotransmitter-mediateddisorder includes schizophrenia, anxiety, bipolar disorders, psychosisand depression and ADHD. In one variation, depression as used hereinincludes and intends treatment-resistant depression, depression relatedto a psychotic disorder, or depression related to a bipolar disorder. Inanother aspect, the compounds described herein may be used to treat,prevent, delay the onset and/or delay the development of a neuronaldisorder. In one aspect, the compounds described herein may also be usedto treat, prevent, delay the onset and/or delay the development ofcognitive disorders, psychotic disorders, neurotransmitter-mediateddisorders and/or neuronal disorders for which the modulation of anaminergic G protein-coupled receptor is believed to be or is beneficial.

The invention also provides methods of improving cognitive functionsand/or reducing psychotic effects comprising administering to anindividual in need thereof an amount of a compound of the invention or apharmaceutically acceptable salt thereof effective to improve cognitivefunctions and/or reduce psychotic effects. In a particular variation, amethod of treating schizophrenia is provided, wherein the treatmentprovides an improvement in at least one cognitive function, such as animprovement in a cognitive function in an individual who has or issuspected of having CIAS. In a further variation, a method of treatingschizophrenia is provided wherein the method reduces psychotic effectsassociated with schizophrenia. In one embodiment, a method of treatingschizophrenia is provided wherein the method improves the negativesymptoms of schizophrenia in an individual in need thereof. In oneembodiment, a method of treating schizophrenia is provided wherein themethod improves the positive symptoms of schizophrenia in an individualin need thereof. In a further variation, a method of treatingschizophrenia is provided wherein the method both improves cognitivefunction and reduces psychotic effects in an individual in need thereof.A method of improving one or more negative, positive and disorganizedsymptoms of schizophrenia is also provided, where the method entailsadministering a compound as detailed herein, or a pharmaceuticallyacceptable salt thereof, to an individual in need of such improvement.In one variation, a method of improving at least one negative symptom ofschizophrenia is provided, where the method entails administering acompound as detailed herein, or a pharmaceutically acceptable saltthereof, to an individual in need of such improvement. In anothervariation, a method of improving at least one negative and at least onepositive symptom of schizophrenia is provided, where the method entailsadministering a compound as detailed herein, or a pharmaceuticallyacceptable salt thereof, to an individual in need of such improvement.In yet another variation, a method of improving at least one negativeand at least one disorganized symptom of schizophrenia is also provided,where the method entails administering a compound as detailed herein, ora pharmaceutically acceptable salt thereof, to an individual in need ofsuch improvement. In still another variation, a method of improving atleast one positive and at least one disorganized symptom ofschizophrenia is also provided, where the method entails administering acompound as detailed herein, or a pharmaceutically acceptable saltthereof, to an individual in need of such improvement. In still afurther variation, a method of improving at least one negative, at leastone positive and at least one disorganized symptom of schizophrenia isprovided, where the method entails administering a compound as detailedherein, or a pharmaceutically acceptable salt thereof, to an individualin need of such improvement.

The invention also provides methods of stimulating neurite outgrowthand/or promoting neurogenesis and/or enhancing neurotrophic effects inan individual comprising administering to an individual in need thereofan amount of a compound of the invention or a pharmaceuticallyacceptable salt thereof effective to stimulate neurite outgrowth and/orto promote neurogenesis and/or to enhance neurotrophic effects.

The invention further encompasses methods of modulating an aminergic Gprotein-coupled receptor comprising administering to an individual inneed thereof an amount of a compound of the invention or apharmaceutically acceptable salt thereof effective to modulate anaminergic G protein-coupled receptor.

It is to be understood that methods described herein also encompassmethods of administering compositions comprising the compounds of theinvention.

Methods for Treating, Preventing, Delaying the Onset, and/or Delayingthe Development Cognitive Disorders, Psychotic Disorders,Neurotransmitter-Mediated Disorders and/or Neuronal Disorders

In one aspect, the invention provides methods for treating, preventing,delaying the onset, and/or delaying the development of cognitivedisorders, psychotic disorders, neurotransmitter-mediated disordersand/or neuronal disorders for which the modulation of an aminergic Gprotein-coupled receptor is believed to be or is beneficial, the methodcomprising administering to an individual in need thereof a compound ofthe invention. In some variations, modulation of adrenergic receptorα_(1D), α_(2A), α_(2B), serotonin receptor 5-HT_(2A), 5-HT₆, 5-HT₇,histamine receptor H₁ and/or H₂ is expected to be or is beneficial forthe cognitive disorders, psychotic disorders, neurotransmitter-mediateddisorders and/or neuronal disorders. In some variations, modulation ofadrenergic receptor α_(1D), α_(2A), α_(2B) and a serotonin receptor5-HT₆ receptor is expected to be or is beneficial for the cognitivedisorders, psychotic disorders, neurotransmitter-mediated disordersand/or neuronal disorders. In some variations, modulation of adrenergicreceptor α_(1D), α_(2A), α_(2B), and a serotonin receptor 5-HT₆ receptorand modulation of one or more of the following receptors serotonin5-HT₇, 5-HT_(2A), 5-HT_(2C) and histamine H₁ and H₂ is expected to be oris beneficial for the cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders. In somevariations, modulation of a dopamine receptor D₂ is expected to be or isbeneficial for the cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders. In somevariations, modulation of dopamine receptor D_(2L) is expected to be oris beneficial for the cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders. Incertain variations, modulation of a dopamine D₂ receptor and serotoninreceptor 5-HT_(2A) is expected to be or is beneficial for the cognitivedisorders, psychotic disorders, neurotransmitter-mediated disordersand/or neuronal disorders. In certain variations, modulation of adopamine D_(2L) receptor and serotonin receptor 5-HT_(2A) is expected tobe or is beneficial for the cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders. In somevariations, the cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders aretreated, prevented and/or their onset or development is delayed byadministering a compound of the invention.

Methods to Improve Cognitive Functions and/or Reduce Psychotic Effects

The invention provides methods for improving cognitive functions byadministering a compound of the invention to an individual in needthereof. In some variations, modulation of one or more of adrenergicreceptor α_(1D), α_(2A), α_(1D), serotonin receptor 5-HT_(2A), 5-HT₆,5-HT₇, histamine receptor H₁ and/or H₂ is desirable or expected to bedesirable to improve cognitive functions. In some variations modulationof α_(1D), α_(2A), α_(2B) adrenergic receptors and a serotonin 5-HT₆receptor is desirable or expected to be desirable to improve cognitivefunctions. In some variations, modulation of α_(1D), α_(2A), α_(2B)adrenergic receptors and serotonin receptor 5-HT₆ and modulation of oneor more of the following receptors: serotonin receptor 5-HT₇, 5-HT_(2A),5-HT_(2C) and histamine receptor H₁ and H₂, is desirable or expected tobe desirable to improve cognitive functions. In another aspect, theinvention encompasses methods to reduce psychotic effects byadministering a compound of the invention to an individual in needthereof. In some embodiments, modulation of a dopamine D₂ receptor isexpected to be or is desirable to reduce psychotic effects. In someembodiments, modulation of a dopamine D_(2L) receptor is expected to beor is desirable to reduce psychotic effects. In some embodiments,modulation of a dopamine D₂ receptor and a serotonin 5-HT_(2A) receptoris expected to be or is desirable to reduce psychotic effects. In somevariations, a compound of the invention is administered to an individualin need thereof. In some embodiments, modulation of a dopamine D_(2L)receptor and a serotonin 5-HT_(2A) receptor is expected to be or isdesirable to reduce psychotic effects. In some variations, a compound ofthe invention is administered to an individual in need thereof.

Methods to Stimulate Neurite Outgrowth, Promote Neurogenesis and/orEnhance Neurotrophic Effects

In a further aspect, the invention provides methods of stimulatingneurite outgrowth and/or enhancing neurogenesis and/or enhancingneurotrophic effects comprising administering a compound of theinvention or pharmaceutically acceptable salt thereof under conditionssufficient to stimulate neurite outgrowth and/or to enhance neurogenesisand/or enhance neurotrophic effects to an individual in need thereof. Insome variations, a compound of the invention stimulates neuriteoutgrowth at a potency of about 1 μM as measured in a suitable assaysuch as the assays described herein. In some variations, a compound ofthe invention stimulates neurite outgrowth at a potency of about 500 nMas measured in a suitable assay such as the assays described herein. Insome variations, a compound of the invention stimulates neuriteoutgrowth at a potency of about 50 nM as measured in a suitable assaysuch as the assays described herein. In some variations, a compound ofthe invention stimulates neurite outgrowth at a potency of about 5 nM asmeasured in a suitable assay such as the assays described herein.

Methods to Modulate an Aminergic G Protein-Coupled Receptor

The invention further contemplates methods for modulating the activityof an aminergic G-protein-coupled receptor comprising administering acompound of the invention or pharmaceutically acceptable salt thereofunder conditions sufficient to modulate the activity of an aminergic Gprotein-coupled receptor. In some variations, the aminergic Gprotein-coupled receptor is a α_(1D), α_(2A), α_(2B) adrenergic receptorand a serotonin 5-HT₆ receptor. In some variations, the aminergic Gprotein-coupled receptor is a α_(1D), α_(2A), α_(2B) adrenergic receptorand a serotonin 5-HT₆ and 5-HT₇ receptor. In some variations, theaminergic G protein-coupled receptor is a α_(1D), α_(2A), α_(2B)adrenergic receptor, a serotonin 5-HT₆ and one or more of the followingreceptors: serotonin 5-HT₇, 5-HT_(2A) and 5-HT_(2C) and histamine H₁ andH₂ receptor. In some variations, the aminergic G protein-coupledreceptor is a dopamine D_(2L) receptor. In some variations, theaminergic G protein-coupled receptor is a dopamine D_(2L) receptor and aserotonin 5-HT_(2A) receptor. In some variations, the aminergic Gprotein-coupled receptor is a histamine H₁ receptor.

Dose-Dependent Therapy (DDT)

Dose dependent therapy refers to the concept that a single molecule maybe used for different indications depending on the dose at which it isadministered. It has been shown that compounds included in the inventionexert pro-cognitive effects (where in one aspect pro-cognitive effectsare achieved by reducing one or more symptoms associated with impairedcognition) when administered at low dose, whereas at high dose, thesecompounds induce both pro-cognitive and anti-psychotic effects (where inone aspect anti-psychotic effects are achieved by reducing one or moresymptoms associated with a psychotic disorder). These compounds arefurther referred to as Dose-Dependent Therapy compounds (DDT compounds).When administered at high dose, DDT compounds in one aspect show fewerand/or lesser side-effects such as, e.g., extrapyramidal syndrome (EPS),as compared to other anti-psychotics, such as anti-psychotics which arenot 5-HT_(2A) receptor modulators. It is believed that EPS is caused, atleast in part, by high D₂ receptor occupancy, the effect of which can becounteracted by compounds displaying a high affinity to the serotoninreceptor 5-HT_(2A). EPS can be determined using various scales known inthe art such as the Abnormal Involuntary Movement Scale (AIMS), BarnesAkathisia Rating Scale (BARS), Simpson-Angus Rating Scale (SARS),Extrapyramidal Symptoms Rating Scale (ESRS) and the ExtrapyramidalSymptoms Rating Scale-Abbreviated (ESRS-A). DDT compounds in one aspectare 5-HT_(2A) modulators, and preferably are antagonists of 5-HT_(2A).In one variation, DDT compounds have low or no affinity for thehistamine receptor H₁, which is also implicated in undesirable sideeffects such as metabolic syndrome, diabetes type 2, weight gain,hyperlipidemia, hyperglycemia, hypertension and drowsiness (Kroeze etal., Neuropsychopharmacology (2003) 28, 519-526).

DDT Compounds

DDT compounds modulate at least serotonin receptor 5-HT_(2A) and/orserotonin receptor 5-HT₆ and modulate dopamine receptor D₂, such asD_(2L). In one aspect, DDT compounds inhibit binding of a ligand to atleast 5-HT_(2A) and/or 5-HT₆ and binding of a ligand to D₂. Inhibitionof binding for all variations detailed herein is determined in asuitable assay known in the art, such as the assays described herein. Inone aspect, DDT compounds act as antagonists of 5-HT_(2A) and/or 5-HT₆and act as antagonists of D₂. In another aspect, DDT compounds act asantagonists of 5-HT_(2A) and D₂. In another aspect, DDT compounds act asantagonists of 5-HT_(2A), 5-HT₆ and D₂. In one variation, DDT compoundsinhibit binding of a ligand to 5-HT_(2A) and/or 5-HT₆ by at least about50% at a DDT concentration of about 0.1 μM and inhibit binding of aligand to D₂ by at least about 90% at a DDT concentration of about 1 μM.In another variation, DDT compounds inhibit binding of a ligand to5-HT_(2A) and/or 5-HT₆ by greater than about any of 50%, 60%, 70% or 80%at a DDT concentration of at least about 0.1 μM. In a further variation,DDT compounds inhibit binding of a ligand to 5-HT_(2A) and/or 5-HT₆ bygreater than about any of 50%, 60%, 70% or 80% at a DDT concentration ofless than about 0.1 μM (e.g., greater than about 0.01 μM and less thanabout 0.1 μM). In a further variation, DDT compounds inhibit binding ofa ligand to 5-HT_(2A) and/or 5-HT₆ by at least about 80% at a DDTconcentration of about 0.1 μM. In one variation, DDT compounds inhibitbinding of a ligand to D₂ by at least about 90% at a DDT concentrationof greater than about In another variation, DDT compounds inhibitbinding of a ligand to D₂ by at least about 90% at a DDT concentrationof between about 1 μM to about 3 μM. In one variation, DDT compoundsinhibit binding of Ketanserin, LSD and Spiperone to 5-HT_(2A), 5-HT₆ andD₂, respectively, as determined in the assays described herein. Inanother variation, binding of a ligand to 5-HT_(2A) and/or 5-HT₆ isinhibited by greater than about any of 80%, 85%, 90% or 95%, or by about100% at a DDT concentration of about 0.1 μM. In a further variation,binding of a ligand to 5-HT_(2A) and/or 5-HT₆ is inhibited between about85% to about 95% or between about 90% to about 100% at a DDTconcentration of about 0.1 μM. In another variation, binding of a ligandto D₂ is inhibited by greater than about any of 90% and 95%, or by about100% at a DDT concentration of about 1 μM. In a further variation,binding of a ligand to D₂ is inhibited by between about 90% to about100% at a concentration of about 1 μM. In another variation, inhibitionof binding of a ligand to 5-HT_(2A) and/or 5-HT₆ is at least 80%±20% ata DDT concentration of about 0.1 μM and binding of a ligand to D₂ isinhibited by at least about 90% at a concentration of about 1 μM asdetermined in assays known in the art. In one aspect, DDT compoundsinhibit binding of a ligand to 5-HT_(2A) and D₂. In another aspect, DDTcompounds inhibit binding of a ligand to 5-HT₆ and D₂. In yet anotheraspect, DDT compounds inhibit binding of a ligand to 5-HT_(2A), 5-HT₆and D₂. In one variation, percent inhibition of binding to 5-HT_(2A),5-HT₆ and D₂ is measured by assays detailed herein.

In one aspect, DDT compounds display low affinity to histamine receptorH₁. Compounds with low affinity to H₁ are those compounds which displayless than about 80% inhibition of binding of a ligand to H₁. Inhibitionof binding of a ligand to H₁ for all variations detailed herein isdetermined by a suitable assay known in the art such as the assaydescribed herein. In some variations, DDT compounds inhibit binding of aligand to H₁ by less than about any of 80%, 75%, 70%, 65%, 60% 55% or50%. In one variation, DDT compounds inhibit binding of a ligand to H₁by between about 50% to about 80%. In some variations, DDT compoundsinhibit binding by less than about 80% at any DDT concentration, e.g.,at about 0.1 μM to about 1 μM. In one variation, DDT compounds inhibitbinding of Pyrilamine to H1 as determined in the assay described herein.In a further variation, percent inhibition of binding to H₁ is measuredby assays detailed herein.

In some aspects, DDT compounds act as 5-HT_(2A) and D₂ antagonists.Antagonist activity for all variations is measured in suitable assaysknown in the art such as the assays described herein. In one variation,5-HT_(2A) activity is inhibited by at least about 70% at a DDTconcentration of about 0.1 μM. In another variation, 5-HT_(2A) activityis inhibited by greater than about any of 70%, 75%, 80%, 85%, 90%, or95%, or by about 100% at a DDT concentration of about 0.1 μM. In onevariation, D₂ activity is inhibited by at least about 70% at a DDTconcentration of about 1 μM. In another variation, D₂ activity isinhibited by greater than about any of 70%, 75%, 80%, 85%, 90%, or 95%,or by about 100% at a DDT concentration of about 1 μM. In one variation,percent inhibition of activity is determined in the assays describedherein. In one aspect, DDT compounds inhibit 5-HT_(2A) and D₂ activity.In another aspect, DDT compounds inhibit 5-HT_(2A), 5-HT₆ and D₂activity.

In one aspect, DDT compounds display any of the activities detailedherein for DDT compounds and further have a structure of the formulaeprovided herein. In one aspect, DDT compounds contain a substitutedvinyl moiety, such as a methylvinyl moiety. Accordingly, in a particularaspect, DDT compounds are of the formula (C), or any variation thereof,including compounds of the formula (C), where at least one of R^(8d) andR^(8f) is other than H, such as when at least one of R^(8d) and R^(8f)is a C₁-C₈ alkyl, C₃-C₈ cycloalkyl, or C₁-C₈ perhaloalkyl. DDT compoundsmay also be of the formulae (X-1), (X-1a), (X-1b), (X-2), (X-2a),(X-2b), (X-3), (X-4), (X-5), (X-6), (X-7), (X-8), (X-9) or (X-10), orany variation thereof. DDT compounds may also be of the formulae (C-1),(C-1a), (C-1b), (C-2), (C-2a), (C-2b), (C-3a), (C-3b), (C-4a), (C-4b),(C-5a), (C-5b), (C-6a) or (C-6b).

DDT compounds may be present as pharmaceutically acceptable salts, orsolvates thereof. Pharmaceutical compositions comprising a DDT compoundand a pharmaceutically acceptable carrier are also embraced. Thesepharmaceutical compositions may take a form suitable for oral, buccal,parenteral, nasal, topical or rectal administration or a form suitablefor administration by inhalation.

High Dose

In one aspect, high dose of a DDT compound corresponds to an amount thatresults in at least 65% of receptor occupancy of dopamine receptor D₂,which may be assessed by known methods, such as Positron EmissionTomography (PET) (Pani et al., European Psychiatry (2007) 22, 276-275).In some variations, a high dose provides D₂ occupancy that is greaterthan any one of 65%, 70%, 75%, 80%, 85% and 90%. In one variation, ahigh dose provides D₂ occupancy that is at least 65%. In anothervariation, a high dose provides a D₂ occupancy that is from at least 65%to 90%, or from at least 65% to 85%, or from at least 65% to 80%, orfrom at least 65% to 75%, or from at least 65% to 70%, or from at least70% to 90%, or from at least 70% to 85%, or from at least 70% to 80%, orfrom at least 70% to 75%, or from at least 75% to 90%, or from at least75% to 85%, or from at least 75% to 80%, or from at least 80% to 90%. Inone variation, a high dose provides D₂ occupancy that is less than 80%and greater than 65%.

In another aspect, high dose of a DDT compound corresponds to a dailydose of at least about 1 mg/kg. In another variation, high dosecorresponds to a daily dose of about 1 mg/kg. In another variation, highdose corresponds to a daily dose of at least about 1 mg/kg to at leastabout 3 mg/kg. In yet another variation, high dose corresponds to adaily dose of at least about 1 mg/kg to about 5 mg/kg. In a furthervariation, high dose corresponds to a daily dose of greater than 1mg/kg.

In a further aspect, high dose of a DDT compound corresponds to anamount that induces anti-psychotic effects as determined by the Positiveand Negative Syndrome Scale (PANSS). In another variation,anti-psychotic effects are measured by one or more of the following:PANSS, Brief Psychiatric Rating Scale (BPRS), Positive symptom sub-scaleof PANSS, Young Mania Rating Scale (Y-MRS), Mania Rating Scale (MRS). Ina further variation, anti-psychotic effects are measured by anotherscale and/or test known in the art.

In another aspect of the invention, high dose of a DDT compoundcorresponds to at least about 100 times the amount that inducespro-cognitive effects but does not induce anti-psychotic effects. In onevariation, pro-cognitive effects are determined by cognition scalesknown in the art such as the Measurement and Treatment Research toImprove Cognition in Schizophrenia MATRICS. In another variation,pro-cognitive effects are determined by measuring the cognitivecomponents of one or more of the following scales and/or tests: MATRICS,Negative Symptoms Assessment scale (NSA), Scale for the Assessment ofNegative Symptoms (SANS), Schedule for the Deficit Syndrome (GDS),Negative symptom sub-scale of PANSS, MATRICS Consensus Cognition Battery(MCCB), CNSVitalSigns, CogState battery, Cognitive Drug Research battery(CDR), Brief Assessment of Cognition in Schizophrenia (BACS),Schizophrenia Cognition Rating Scale (SCoRS), Clinical Global Impressionof Cognition in Schizophrenia (CGI-CogS), Repeatable Battery for theAssessment of Neuropsychological Status (RBANS), Test of AdaptiveBehavior in Schizophrenia (TABS), Independent Living Skills Inventory(ILS), UCSD Performance-Based Skills Assessment (UPSA), CognitiveAssessment Interview (CAI), Global Assessment of Function from CAI(GAF), Quality of Life Scale (QLS), Maryland Assessment of SocialCompetence (MASC), Calgary Depression Scale (CDS), and Montgomery-ÅsbergDepression Rating Scale (MADRS). In a further variation, pro-cognitiveeffects are determined by another scale and/or test known in the art.

Low Dose

In one aspect, low dose of a DDT compound corresponds to an amount thatresults in less than 65% receptor occupancy of dopamine receptor D₂. Insome variations, a low dose provides D₂ occupancy that is less than anyone of 65%, 60%, 55% and 50%.

In another aspect, low dose of a DDT compound corresponds to a dailydose of about 0.03 mg/kg. In another variation, low dose corresponds toa daily dose of about 0.03 to about 0.3 mg/kg. In another variation, lowdose corresponds to a daily dose of about 0.3 mg/kg. In yet anothervariation, low dose corresponds to a daily dose of about 0.03 to about 1mg/kg. In a further variation, low dose corresponds to a daily dose ofabout 0.01 mg/kg. In yet another variation, low dose corresponds to adaily dose of 0.01 to about 1 mg/kg. In a further variation, low dosecorresponds to a daily dose of about 0.5 mg/kg. In yet anothervariation, low dose corresponds to a daily dose of less than about 0.5mg/kg. In another variation, low dose corresponds to a daily dose ofless than 1 mg/kg.

In a further aspect, low dose of a DDT compound corresponds to an amountthat induces pro-cognitive effects as determined by cognition scalessuch as MATRICS but does not induce anti-psychotic effects. In anothervariation, pro-cognitive effects are determined by measuring thecognitive components of one or more of the following scales and/ortests: MATRICS, Negative Symptoms Assessment scale (NSA), Scale for theAssessment of Negative Symptoms (SANS), Schedule for the DeficitSyndrome (GDS), Negative symptom sub-scale of PANSS, MATRICS ConsensusCognition Battery (MCCB), CNSVitalSigns, CogState battery, CognitiveDrug Research battery (CDR), Brief Assessment of Cognition inSchizophrenia (BACS), Schizophrenia Cognition Rating Scale (SCoRS),Clinical Global Impression of Cognition in Schizophrenia (CGI-CogS),Repeatable Battery for the Assessment of Neuropsychological Status(RBANS), Test of Adaptive Behavior in Schizophrenia (TABS), IndependentLiving Skills Inventory (ILS), UCSD Performance-Based Skills Assessment(UPSA), Cognitive Assessment Interview (CAI), Global Assessment ofFunction from CAI (GAF), Quality of Life Scale (QLS), MarylandAssessment of Social Competence (MASC), Calgary Depression Scale (CDS),and Montgomery-Åsberg Depression Rating Scale (MADRS). In a furthervariation, pro-cognitive effects are determined by another scale and/ortest known in the art.

In another aspect of the invention, low dose of a DDT compoundcorresponds to at least about 1/100 the amount that inducesanti-psychotic effects. In one variation, anti-psychotic effects aredetermined by assays such as PANSS. In another variation, anti-psychoticeffects are measured by one or more of the following: PANSS, BriefPsychiatric Rating Scale (BPRS), Positive symptom sub-scale of PANSS,Young Mania Rating Scale (Y-MRS), Mania Rating Scale (MRS). In a furthervariation, anti-psychotic effects are measured by another scale and/ortest known in the art.

Unit Dosage Forms

DDT compounds may be provided in various unit dosage forms. In oneaspect, single therapy dosages are provided. In one variation, a unitdosage form comprises a low dose as described herein of a DDT compound.In another variation, a unit dosage form comprises a high dose asdescribed herein of a DDT compound.

In another aspect, combination therapy dosage forms are provided. In onevariation, combination dosage forms comprise a low dose as describedherein of a DDT compound and a second drug suitable for anti-psychotictherapy. In another variation, combination dosage forms comprise a highdose as described herein of a DDT compound and a second drug suitablefor anti-psychotic therapy.

Kits

The present invention further provides for kits comprising DDT compoundswith instructions for achieving pro-cognitive effects at low dose asdetailed herein or pro-cognitive effects and anti-psychotic effects athigh dose as detailed herein. In one aspect, kits comprise a low dose ofa DDT compound and instructions for achieving only pro-cognitiveeffects. In some variations, pro-cognitive effects include (i)improvement of CIAS such as improvement of any one or more of memory(e.g., short term memory, working memory, social memory), attention,impulsivity, verbal fluency and executive function and/or (ii)improvement of negative symptoms of schizophrenia such as improvement ofany one or more of blunted affect, avolition, anhedonia, alogia,dysphoria, suicidality, hopelessness, depression and low mood. Thus,kits for use to achieve pro-cognitive effects in one aspect comprise alow dose of a DDT compound as described herein. In another variation,kits for use to achieve pro-cognitive effects comprise a unit dosageform containing a low dose of a DDT compound as described herein.

In a further aspect, kits of the present invention comprise a high doseof a DDT compound and instructions for achieving both pro-cognitive andanti-psychotic effects. In some variations, anti-psychotic effectscomprise improvement of any one or more of psychotic symptoms such aspositive symptoms of schizophrenia (e.g., delusions, hallucinations,disorganized thought and agitation). Kits comprising a high dose of aDDT compound may be used to achieve one or more pro-cognitive effectsand one or more anti-psychotic effects. Thus, kits for use to achievepro-cognitive and anti-psychotic effects in one aspect comprise a highdose of a DDT compound as described herein. In another variation, kitsfor use to achieve pro-cognitive and anti-psychotic effects comprise aunit dosage form containing a high dose of a DDT compound as detailedherein. In a further variation, kits for use to achieve pro-cognitiveand anti-psychotic effects comprise a low dose of a DDT compound and asecond drug suitable for anti-psychotic therapy. In yet anothervariation, kits for use to achieve pro-cognitive and anti-psychoticeffects comprise a high dose of a DDT compound and a second drugsuitable for anti-psychotic therapy. In one aspect, kits for use toachieve pro-cognitive and anti-psychotic effects comprise DDT compoundsin unit dosage forms as detailed herein.

Methods of Treatment

The invention provides methods of treating diseases or conditions inwhich cognition and/or psychosis are implicated. The present inventionprovides methods of treating cognitive disorders and/or psychoticdisorders by administering a DDT compound at a pharmaceuticallyeffective dose to a subject in need thereof. In one variation, cognitivedisorder as used herein includes and intends disorders that contain acognitive component, such as psychotic disorders (e.g., schizophrenia)containing a cognitive component (e.g., CIAS). In one variation, acognitive disorder is a disorder which affects executive function. Inone variation, psychotic disorder as used herein includes and intendsdisorders that contain a psychotic component, for example cognitivedisorders (e.g., Alzheimer's disease) that contain a psychotic component(e.g., psychosis of Alzheimer's Disease or dementia). In one variation,a psychotic disorder is psychosis associated with dementia.

In one aspect, the present invention encompasses methods of improvingcognition by administering a DDT compound at a pharmaceuticallyeffective dose to a subject in need thereof. In one variation, improvingcognition comprises reducing one or more symptoms associated withimpaired cognition. In a further aspect, the present invention providesmethods of (i) improving cognition and (ii) reducing symptoms associatedwith psychotic disorders in a subject in need thereof. In yet anotheraspect, the present invention encompasses methods of improving cognitionand not reducing symptoms associated with psychotic disorders in asubject in need thereof. In yet a further aspect, the present inventionprovides methods of improving cognition and not significantly reducingsymptoms associated with psychotic disorders in a subject in needthereof. In some variations, a subject in need thereof is an individualwho is refractory to other pro-cognitive and/or anti-psychotic therapy.

In one aspect, the invention is directed to methods of improvingcognition and/or reducing symptoms associated with impaired cognition byadministering a DDT compound at either low or high dose. In onevariation improving cognition comprises (i) improvement of CIAS such asimprovement of any one or more of memory (e.g., short term memory,working memory, social memory), attention, impulsivity, verbal fluencyand executive function and/or (ii) improvement of negative symptoms ofschizophrenia such as improvement of any one or more of blunted affect,avolition, anhedonia, alogia, dysphoria, suicidality, hopelessness,depression and low mood.

In a further aspect, the invention provides methods of both (i)improving cognition (e.g., as set forth herein) and/or reducing symptomsassociated with impaired cognition and (ii) reducing symptoms associatedwith psychotic disorders by administering a DDT compound at high dose.In one variation, reducing symptoms associated with psychotic disorderscomprises improvement of any one or more of psychotic symptoms such aspositive symptoms of schizophrenia (e.g., delusions, hallucinations,disorganized thought and agitation). In one variation, the invention isdirected to methods of treating schizophrenia by administering a highdose of a DDT compound. In another variation, the invention providesmethods of reducing one or more symptom of positive symptoms ofschizophrenia by administering a high dose of a DDT compound. In afurther variation, the invention encompasses methods of reducing one ormore symptom of positive and/or one or more symptom of negative symptomsof schizophrenia by administering a high dose of a DDT compound. In yetanother variation, the invention provides methods of reducing one ormore symptom of positive symptoms and/or one or more symptom of CIAS byadministering a high dose of a DDT compound. In yet another variation,the invention provides methods of reducing one or more symptom ofpositive symptoms and/or one or more symptom of negative symptoms and/orone or more of disorganized symptoms of schizophrenia by administering ahigh dose of a DDT compound.

In another aspect, the invention is directed to methods of improvingcognition and/or reducing symptoms associated with impaired cognitionand not reducing symptoms associated with psychotic disorders byadministering a DDT compound at low dose. In one variation improvingcognition comprises (i) improvement of CIAS such as improvement of anyone or more of memory (e.g., short term memory, working memory, socialmemory), attention, impulsivity, verbal fluency and executive functionand/or (ii) improvement of negative symptoms of schizophrenia such asimprovement of any one or more of blunted affect, avolition, anhedonia,alogia, dysphoria, suicidality, hopelessness, depression and low mood.

In yet another aspect, the invention encompasses methods of improvingcognition and/or reducing symptoms associated with impaired cognitionwithout significantly improving symptoms associated with psychoticdisorders by administering a DDT compound at low dose.

Methods of Manufacturing a Medicament

In a further aspect of the invention use of DDT compounds andcompositions thereof in the manufacture of a medicament is provided.Particularly, the manufacture of a medicament for use in the treatmentof diseases or conditions in which cognition and/or psychosis areimplicated are described herein. Further, pharmaceutical compositions ofDDT compounds are also intended for use in the manufacture of amedicament for use in treatment of diseases or conditions in whichcognition and/or psychosis are implicated.

Method of Determining a Dose/Treatment

The present invention further encompasses methods of determining asuitable or optimal dose of a DDT compound to either (i) achievepro-cognitive effects alone or (ii) achieve both pro-cognitive effectsand anti-psychotic effects in an individual in need thereof. In oneaspect, a suitable dose is determined by measuring the percentage of D₂occupancy and adjusting an individual's dosage in response thereto. Inone variation, dosage is increased to achieve anti-psychotic effects ifD₂ occupancy is less than 65% as determined by methods known in the artsuch as PET. In another variation, dosage is increased to achieveanti-psychotic effects if D₂ occupancy is less than any one of 65%, 60%,55%, and 50%. In a further variation, dosage is reduced to achievepro-cognitive and not anti-psychotic effects if D₂ occupancy is at least65%. In yet another variation, dosage is reduced to achievepro-cognitive and not anti-psychotic effects if D₂ occupancy is atgreater than any one of 65%, 70%, 75%, 80% and 90%. In a furthervariation, dosage is reduced to achieve pro-cognitive and no significantanti-psychotic effects if D₂ occupancy is greater than 65%. Oneindication of at least 65% D₂ occupancy or greater than any one of 65%,70%, 75%, 80% and 90% D₂ occupancy is the reduction in the number orseverity of one or more symptoms associated with a psychotic disorder.

In another aspect, a suitable dose is determined by assessingpro-cognitive and/or anti-psychotic effects in an individual andadjusting an individual's dosage in response thereto. For example, inone variation, an individual's dosage is increased from a first dosageto a higher, second dosage, in order to achieve anti-psychotic effectsat the second dosage level, if it is determined that the first dosagedoes not induce anti-psychotic effects in the individual, as may beassessed by suitable test and/or scales known in the art. In anothervariation, dosage is reduced from a first dosage to a lower, seconddosage wherein the second dosage still achieves anti-psychotic effectsbut reduces side effects as compared to the first dosage. Side effectsmay be determined by suitable tests and/or scales known in the art. Inanother variation, dosage is decreased from a first dosage to a lower,second dosage, in order to achieve pro-cognitive and not anti-psychoticeffects. In another variation, dosage is decreased from a first dosageto a lower, second dosage, in order to achieve pro-cognitive and notanti-psychotic effects and wherein the dosage induces fewer or lesserside effects than the first dosage. Thus, in yet another variation,dosage is reduced to a minimum dosage which still achieves pro-cognitiveeffects but reduces side-effects as determined by suitable tests and/orscales.

In one aspect, an individual's therapy is monitored as set forth abovefor a period of time, such as one week, two weeks, three weeks, onemonth, two months, three months, four months, five months, 6 months ormore (such as throughout the course of an individual's therapy), toadjust an individual's dosage level as needed. As such, individualizedtherapy as detailed herein provides for methods of measuring therapeuticparameters and adjusting dosage in response thereto in order to achievean optimal dosage amount according to an individual's initial andcontinued response to therapy.

General Synthetic Methods

The compounds of the invention may be prepared by a number of processesas generally described below and more specifically in the Exampleshereinafter. In the following process descriptions, the symbols whenused in the formulae depicted are to be understood to represent thosegroups described above in relation to formula (I), (Ia), (Ib), (Ic) or(C) or any variation thereof unless otherwise indicated.

Where it is desired to obtain a particular enantiomer of a compound,this may be accomplished from a corresponding mixture of enantiomersusing any suitable conventional procedure for separating or resolvingenantiomers. Thus, for example, diastereomeric derivatives may beproduced by reaction of a mixture of enantiomers, e.g. a racemate, andan appropriate chiral compound. The diastereomers may then be separatedby any convenient means, for example by crystallization and the desiredenantiomer recovered. In another resolution process, a racemate may beseparated using chiral High Performance Liquid Chromatography.Alternatively, if desired a particular enantiomer may be obtained byusing an appropriate chiral intermediate in one of the processesdescribed.

Chromatography, recrystallization and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular isomer of a compound or tootherwise purify a product of a reaction.

The following abbreviations are used herein: thin layer chromatography(TLC); Hour (h); Minute (min.); Second (sec.); Ethanol (EtOH);dimethylsulfoxide (DMSO); N,N-dimethylformamide (DMF); trifluoroaceticacid (TFA); tetrahydrofuran (THF); Normal (N); aqueous (aq.); methanol(MeOH); dichloromethane (DCM); Retention factor (Rf).

A method of synthesizing an intermediate used in the synthesis ofcompounds of the invention is shown as General Method 1. Althoughidentifiers such as R are shown in the methods below, it is understoodthat these moieties apply to the compounds detailed herein even ifdifferent identifiers or variations thereof are used elsewhere. It isalso understood that modifications to the specific materials shown inthe methods below are intended, e.g., where a method using a compoundhaving an aryl group such as phenyl can likewise be can utilized with acompound having a heteroaryl group such as pyridyl to arrive atheteroaryl containing products.

General Method 1.

The 1-methylazepan-4-one hydrochloride (1 equiv.) and appropriatelysubstituted arylhydrazine hydrochloride (1 equiv.) are refluxed in amixture of 7% sulfuric acid in 1,4-dioxane (2-3 mL) overnight undernitrogen. The mixture is poured on to ice and basified with 50% aq NaOH.The resulting precipitate is filtered, washed well with water, and driedin air to provide the substituted1,2,3,4,5,6-hexahydroazepino[4,5-b]indole derivative.

A method of synthesizing another intermediate used in the synthesis ofcompounds of the invention is shown as General Method 2.

General Method 2.

The appropriate aryl bromide (1 equiv.) is dissolved in DMF.Tributylvinyltin (1.1 equiv.) and Pd(PPh₃)₄ (0.02 equiv.) are added tothis solution at RT under nitrogen and the reaction mixture is heated at100° C. for 1.5 h. The reaction mixture is cooled to RT, diluted withwater and extracted with DCM. The organic layer is dried over anhydroussodium sulfate and concentrated under reduced pressure below 40° C. Thecrude product is purified through column chromatography in silica gel toprovide the desired vinylarene derivative.

A method of synthesizing another intermediate used in the synthesis ofcompounds of the invention is shown as General Method 3.

General Method 3.

NaH (1 equiv.) is added to DMSO and heated to 65° C. for 1 h. THF isadded at the same temperature and the reaction mixture is heated foranother 10 min., after which the reaction mixture is cooled to 0° C.Trimethylsulfonium iodide (1 equiv.) is then added and the reactionmixture is stirred for 10 min. The solution of appropriate ketone (1equiv.) in THF is added dropwise. After completion of addition, thereaction mixture is stirred at RT for 2 h. The reaction mixture ispoured into ice water and product extracted in diethyl ether, dried overNa₂SO₄ and concentrated at 25° C.

A method of synthesizing certain compounds of the invention is shown asGeneral Method 4.

General Method 4.

A mixture of appropriately substituted1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1 equiv.),2-trifluoromethyl-5-vinylpyridine (1.1 equiv.) and KOH (3.5 equiv.) inNMP (0.5 mL/mmol) is stirred and heated at 50-100° C. for 3 h. Thereaction mixture is cooled to RT and diluted by adding ice and satd.aqueous NaCl. The aqueous mixture is extracted with ethyl acetate andorganic layer is washed with brine, dried over anhydrous sodium sulfateand concentrated under vacuum to obtain crude product. The crude productis purified either by flash chromatography on silica gel or by reversephase HPLC.

A method of synthesizing certain compounds of the invention is shown asGeneral Method 5.

General Method 5.

The appropriately substituted 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(1 equiv.) is dissolved in DMF (2 mL/mmol). To this solution sodiumhydride (2.2 equiv.) is added in portions at RT and stirred for 10 min.The appropriate aryl oxirane (2 equiv.) in DMF (0.5 mL/mmol) is addeddropwise over 10 min. and stirred overnight at RT. The product isdetected by LCMS, and the reaction mixture is quenched with methanol andconcentrated to dryness. Water is added to the residue and product isextracted into ethyl acetate (3×50 mL). The organic layer is dried overanhydrous sodium sulfate and evaporated under reduced pressure. Thecrude product is purified by reverse phase chromatography.

A method of synthesizing certain compounds of the invention is shown asGeneral Method 6.

General Method 6.

The appropriately substituted2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethanol (1 equiv.) istaken into 25% aqueous H₂SO₄ (8 mL/mmol), and stirred at 90° C. for 3 h.The reaction is monitored by TLC and LCMS. The reaction mixture iscooled and basified with aq. KOH solution and extracted with ethylacetate. The organic layer is dried over anhydrous sodium sulfate andevaporated under reduced pressure. The crude product is purified usingreverse phase chromatography.

A method of synthesizing certain compounds of the invention is shown asGeneral Method 7.

General Method 7.

The appropriately substituted 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(1 equiv.), is taken into DMF. CuI (0.1 equiv.), L-proline (0.2 equiv.)and K₃PO₄ (2 equiv.) are added to the solution and the mixture stirredfor 10 min. at RT. The 2-haloacetamide derivative (1.2 equiv.) is addeddropwise. The reaction mixture is heated at 90° C. for 12 h. Aftercompletion of reaction, the reaction mixture is filtered through Celite.DMF is evaporated under reduced pressure and then the residue extractedwith ethyl acetate. The organic layer is dried over anhydrous Na₂SO₄,and concentrated under reduced pressure to obtain the crude product thatis purified by column chromatography.

A method of synthesizing certain compounds of the invention is shown asGeneral Method 8.

General Method 8.

Sodium hydride (1.5 equiv.) is washed with hexane for removal of oil anddried under vacuum. It is then suspended in THF. To this suspensioncarboline (1 equiv.) in THF is added dropwise at 0° C. Then the reactionmixture is stirred for 0.5 h. A solution of vinyl compound (2 equiv.) inTHF is added dropwise into the reaction mixture. The reaction mixture isstirred at RT for 2 h and monitored by TLC. After completion ofreaction, the reaction mixture is quenched with ice-water. The crudecompound is purified by preparative TLC. The pure compound is stirred inethanolic HCl to give the corresponding HCl salt.

A method of synthesizing certain compounds of the invention is shown asGeneral Method 9.

General Method 9.

The substituted carboline (1 equiv.) is taken into DMF. CuI (9 mg, 0.046mmol), L-proline (0.2 equiv.) and K₃PO₄ (2 equiv.) are added to thesolution and the mixture stirred for 10 min. at RT. The 2-chloroacetate(1.2 equiv.) is added dropwise. The reaction mixture is heated at 90° C.for 12 h. After completion of reaction, the reaction mixture is filteredthrough Celite. DMF is evaporated under reduced pressure and the residueextracted with ethyl acetate. The organic layer is dried over Na₂SO₄,and concentrated under reduced pressure. Then the purified compound istaken in ethanol in HCl to give HCl salt of desired compound.

A method of synthesizing another intermediate used in the synthesis ofcompounds of the invention is shown as General Method 10.

General Method 10.

The appropriately substituted azepan-4-one hydrochloride (1 equiv.) andappropriately substituted arylhydrazine hydrochloride (1 equiv.) arerefluxed in a mixture of 7% sulfuric acid in 1,4-dioxane overnight undernitrogen. The mixture is poured on to ice and basified with 50% aq NaOH.The resulting precipitate is filtered, washed well with water, and driedin air to provide the substituted1,2,3,4,5,6-hexahydroazepino[4,5-b]indole derivative.

A method of synthesizing compounds of the invention is shown in GeneralMethod 11.

General Method 11.

In general, a suitably substituted hydrazine A can be reacted with anappropriately substituted alkyl halide B to generate a substitutedhydrazine C, where the internal nitrogen on the hydrazine issubstituted, as shown above. The reaction of intermediate D with anappropriately substituted azepan-4-one D should provide structures ofthe type generally described by structure E.

General Method 12.

Appropriate alcohol-carboline (1 equiv.) is dissolved in DCM and thesolution is cooled to 0° C. Diethylaminosulfur trifluoride (DAST) (1.5equiv.) is added dropwise and the reaction mixture is stirred at RT for2 h. The reaction mixture is diluted with saturated aqueous NaHCO₃solution and the organic layer is separated. The organic layer is driedover anhydrous sodium sulfate and evaporated under reduced pressure. Theresidue is purified by chromatography on neutral alumina to give thefluorinated product.

General Method 13

To a solution of appropriate carboline (1 equiv.) inN-methyl-2-pyrrolidone is added KOH (7 equiv.). The reaction mixture isstirred at RT for 20 min. A solution of appropriate2-bromo-1-(aryl)ethanone (1 equiv.) in N-methyl-2-pyrrolidone is addeddropwise and stirring is continued for additional 2-4 h. The reaction ismonitored by LCMS and TLC. The reaction mixture is diluted by addingwater and extracted with ethyl acetate. The organic layer is washed withwater, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue is purified by silica gel chromatographyto give the keto product.

General Method 14

The keto compound from General Method 13 (1 equiv.) is dissolved inanhydrous THF. Grignard reagent (3 equiv) is added to it dropwise at RTunder nitrogen atmosphere and reaction mixture is stirred at RT for 1 h.Water is added to the reaction mixture and the product is extracted withethyl acetate. The organic layer is washed with water, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue is purified by HPLC to give pure alcohol product.

General Method 15

Appropriately substituted carboline (1 equiv.) is dissolved in DMF (2 mLper mmol) and sodium hydride (2 equiv.) is added to it under nitrogenatmosphere. An appropriate 2-(bromomethyl)-1,3-dioxolane (1 equiv.) isadded and the reaction mixture is heated at 100° C. overnight. Thereaction mixture is diluted by adding water and extracted with ethylacetate. The organic layer is washed with water, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue ispurified by silica gel chromatography to give pure dioxolanyl product.

The methods detailed above may be adapted as known by those of skill inthe art. Particular examples of each General Method are provided in theExamples below. Additional synthetic methods which may be adapted toarrive at the compounds detailed herein are found in U.S. applicationSer. No. 12/259,234 and PCT Application No. PCT/US2008/081390, bothfiled Oct. 27, 2008.

The following Examples are provided to illustrate but not limit theinvention.

All references disclosed herein are incorporated by reference in theirentireties.

EXAMPLES Example 1 Preparation of9-chloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole

The title compound was prepared by following general procedure 1.1-Methylazepan-4-one hydrochloride (164 mg, 1 mmol) and4-chlorophenylhydrazine hydrochloride (179 mg, 1 mmol) were heated in amixture of 7% sulfuric acid in 1,4-dioxane (2-3 mL) overnight undernitrogen. Two liquid layers persisted throughout the reaction. Themixture was poured on to ice and basified with 50% aq NaOH. Theresulting precipitate was filtered, washed well with water, and dried inair to give 9-chloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indoleas a dark brown solid (183 mg 78% yield).

Example 2 Preparation of1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole

The title compound was prepared by following general procedure 1.p-Tolyl hydrazine hydrochloride (15 g, 94.55 mmol) was taken into 7%H₂SO₄ in 1,4-dioxane (650 mL), 1-methylazepan-4-one. HCl (15.4 g, 94.55mmol) was added and stirred at RT for 10 min. The reaction mixture wasstirred at 80° C. for 14 h. After completion of the reaction, reactionmass was slowly basified with 50% NaOH solution, extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate andevaporated to dryness and purified by column chromatography (silica gel100-200 mesh; eluent: 10% methanol-DCM) to afford3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (5 g).

Example 3 Preparation of 2-ethyl-5-vinyl-pyridine

The title compound was prepared by following general procedure 2.2-Ethyl-5-bromo-pyridine (0.6 g, 0.00322 mol) was dissolved in DMF:THF(3:1 6 mL), and to this solution, tributylvinyltin (1.03 mL, 0.00354mol) and Pd(PPh₃)₄ (0.048 g, 0.000041 mol) were added at RT undernitrogen and the mixture heated at 100° C. for 30 min. After completionof the reaction (TLC), the reaction mixture was cooled to RT and dilutedwith water (60 mL) and extracted with DCM (3×100 mL). The organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure using rotary evaporator below 40° C. The crude was purifiedthrough column chromatography (2% ethylacetate:hexane in silica 100-200mesh, Diameter of column—5.0 cm, Height of silica—approx. 5 inch) toprovide 2-ethyl-5-vinylpyridine as a light yellow liquid (0.4 g, 93%yield).

Example 4 Preparation of 2-isopropyl-5-vinyl-pyridine

The title compound was prepared by following general procedure 2.5-Bromo-2-isopropyl-pyridine (0.75 g, 3.7 mmol) was dissolved in DMF:THF(3:1, 6 mL). Tributylvinyltin (1.2 mL, 4.12 mmol) and Pd(PPh₃)₄ (0.070g, 0.06 mmol) was added to this solution at RT under nitrogen and washeated at 100° C. for 30 min. The reaction mixture was cooled to RT anddiluted with water (60 mL) and extracted with DCM (3×100 mL). Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure below 40° C. The crude was purified throughcolumn chromatography (90% DCM-Hexane in silica 100-200 mesh, Diameterof column—5.0 cm, Height of silica—approx. 5 inch) to provide2-isopropyl-5-vinylpyridine as a light yellow liquid (0.5 g, 90% yield).

Example 5 Preparation of 2-trifluoromethyl-5-vinyl-pyridine

The title compound was prepared by following general procedure 2.5-Bromo-2-trifluoromethylpyridine (2.0 g, 8.8 mmol) was dissolved inDMF:THF (3:1, 12 mL). Tributylvinyltin (3.0 g, 9.68 mmol) and Pd(PPh₃)₄(0.135 g, 0.11 mmol) was added to this solution at RT under nitrogen andwas heated at 100° C. for 2 h. After completion of the reaction (TLC),the reaction mixture was cooled to RT and diluted with water (120 mL)and extracted with ethyl acetate (3×100 mL). The organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressureusing rotary evaporator below 40° C. The crude was purified throughcolumn chromatography (2% ethylacetate:hexane in silica 100-200 mesh,Diameter of column—5.0 cm, Height of silica—approx. 5 inch) to provide2-(trifluoromethyl)-5-vinylpyridine as a light yellow oil (0.8 g, 52%yield).

Example 6 Preparation of methyl 5-vinylpyridine-2-carboxylate

The title compound was prepared by following general procedure 2. Methyl5-bromopyridine-2-carboxylate (4.0 g, 18.5 mmol) was dissolved in 160 mLdioxane. Vinyltributyltin (11.7 g, 37 mmol) was added to this solutionat 25° C., followed by addition of dichlorobis(triphenylphosphine)palladium (1.5 g, mmol). The reaction mixture was degassed and purgedwith nitrogen for 5 min. and then heated at 100° C. for 2 h. Thereaction mixture was evaporated under reduced pressure and the residuewas purified by SiO₂ chromatography (100-200 mesh, eluent: hexane-50%ethyl acetate-hexane gradient). The requisite fractions wereconcentrated below 40° C. under reduced pressure to obtain 2 g of methyl5-vinylpyridine-2-carboxylate as a pale yellow oil (solid at −20° C.).TLC R_(f) 0.3 in 40% Ethyl acetate:Hexane.

Example 7 Preparation of 2-methyl-5-vinyl-pyridine

The title compound was prepared by following general procedure 2.5-Bromo-2-methyl pyridine (5 g, 29.0 mmol) was dissolved in DMF:THF(3:1, 35 mL): tributylvinyltin (10.2 g, 31.9 mmol) and Pd(PPh₃)₄ (0.44g, 0.432 mmol) was added to this solution at RT under nitrogen and washeated at 100° C. for 2 h. After completion of the reaction (TLC), thereaction mixture was cooled to RT and diluted with water (350 mL) andextracted with ethyl acetate (3×200 mL). The organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressureusing rotary evaporator below 40° C. The crude was purified throughcolumn chromatography (6% ethylacetate:hexane in silica 100-200 mesh,Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide2-methyl-5-vinylpyridine as a light yellow oil (1.6 g, 47% yield).

Example 8 Preparation of 3-vinyl pyridine

The title compound was prepared by following general procedure 2.3-Bromo pyridine (3.0 g, 18.9 mmol) was dissolved in DMF (9 mL),tributylvinyltin (6.62 g, 20.8 mmol) and Pd(PPh₃)₄ (0.326 g, 0.282 mol)was added to this solution at RT under nitrogen and heated at 80° C. for3 h. The reaction mixture was cooled to RT, diluted with water (90 mL)and extracted with DCM (3×150 mL). The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure below40° C. The crude was purified through column chromatography (5%ethylacetate:hexane in silica 100-200 mesh, Diameter of column—5.0 cm,Height of silica—approx. 5 inch) to provide the desired compound as alight yellow liquid (0.62 g, 30% yield).

Example 9 Preparation of 2-methyl-5-vinyl-pyrimidine

The title compound was prepared by following general procedure 2.5-Bromo-2-methyl-pyrimidine (1.7 g, 9.87 mmol) was dissolved in DMF:THF(3:1 24 mL). Tributylvinyltin (3.2 mL, 10.8 mmol) and Pd(PPh₃)₄ (0.148g, 0.128 mmol) was added to this solution at RT under nitrogen and washeated at 120° C. for 30 min. The reaction mixture was cooled to RT anddiluted with water (60 mL) and extracted with DCM (3×100 mL). Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure using rotary evaporator below 40° C. The crudewas purified through column chromatography (20% Ethyl acetate-Hexane insilica 100-200 mesh, Diameter of column—5.0 cm, Height of silica—approx.5 inch) to provide 2-methyl-5-vinylpyrimidine a as light yellow liquid(1.1 g, 91% yield).

Example 10 Preparation of 5-vinyl-pyrimidine

The title compound was prepared by following general procedure 2.5-Bromo pyrimidine (0.5 g, 3.2 mmol) was dissolved in DMF (6 mL), tothis solution, tributylvinyltin (1.15 g, 3.5 mmol) and Pd(PPh₃)₄ (0.06g, 0.05 mmol) was added at RT under nitrogen and was heated at 100° C.for 1.5 h. The reaction mixture was cooled to RT and diluted with water(60 mL) and extracted with DCM (3×100 mL). The organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressureusing rotary evaporator below 40° C. The crude was purified throughcolumn chromatography (4% ethylacetate:hexane in silica 100-200 mesh,Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide5-vinylpyrimidine as a light yellow liquid (0.32 g, 95% yield).

Example 11 Preparation of 2-methyl-5-vinyl-pyrazine

The title compound was prepared by following general procedure 2.5-Bromo-2-methyl pyrazine (2.0 g, 11 mmol) was dissolved in DMF:THF(3:1, 24 mL). Tributylvinyltin (3.0 g, 12.6 mmol) and Pd(PPh₃)₄ (0.172g, 0.143 mmol) was added to this solution at RT under nitrogen and washeated at 100° C. for 3 h. The reaction mixture was cooled to RT anddiluted with water (240 mL) and extracted with ethyl acetate (3×150 mL),the combined organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure below 40° C. The crude was purifiedthrough column chromatography (2% ethylacetate:hexane in silica 100-200mesh, Diameter of column—5.0 cm, Height of silica—approx. 5 inch) toprovide 2-methyl-5-vinylpyrazine as a light yellow oil (1.0 g, 71%yield).

Example 12 Preparation of 1-methyl-5-vinylpyridin-2(1H)-one

The title compound was prepared by following general procedure 2. To asolution of 5-bromo-1-methylpyridin-2(1H)-one (2 g, 10.63 mmol) in 20 mLof 1,4-dioxane, dichlorobis(triphenylphosphine)palladium(II) (0.834 g,1.19 mmol) was added at RT and stirred at the same temperature for 5min. Tributylvinyltin (3.46 mL, 1.19 mmol) was added slowly at RT andstirred at 100-105° C. for 2 h. The reaction was monitored by TLC andLCMS. After completion of the starting material, the solvent wasevaporated and the residue purified by column chromatography using 60%ethyl acetate-hexane to afford 1.2 g of1-methyl-5-vinylpyridin-2(1H)-one.

Example 13 Preparation of 2-propyl-5-vinyl-pyridine

The title compound was prepared by following general procedure 2.5-Bromo-2-propyl-pyridine (0.5 g, 2.5 mmol) was dissolved in DMF:THF(3:1, 8 mL). To this solution, tributylvinyltin (1.3 mL, 3.7 mmol) andPd(PPh₃)₄ (0.057 g, 0.05 mmol) was added at RT under nitrogen and washeated at 100° C. for 2 h. The reaction mixture was cooled to RT anddiluted with water (80 mL) and extracted with DCM (3×100 mL), theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure using rotary evaporator below 40° C. The crudewas purified through column chromatography (3% ethylacetate:hexane insilica 100-200 mesh, Diameter of column—2.5.0 cm, Height ofsilica—approx. 5 inch) to provide 2-propyl-5-vinylpyridine as a lightyellow liquid (0.15 g, 41% yield).

Example 14 Preparation of 5-vinylpicolinic acid

The title compound was prepared by following general procedure 2. To asolution of 5-bromo pyridine-2-carboxylic acid (5 g, 24.75 mmol) in 50mL of 1,4-dioxan, dichlorobis(triphenylphosphine)palladium(II) (2.08 g,2.96 mmol) was added at RT and stirred at RT for 5 min. Tributylvinyltin(11.7 g, 36.9 mmol) was added slowly at RT and stirred at 100° C. for 3h. The reaction mixture was monitored by TLC and LCMS. After completionof the starting material, evaporated the solvent below 40° C. andpurified by column chromatography using ethyl acetate to afford the5-vinylpyridine-2-carboxylic acid (3.5 g, 94.5%).

Example 15 Preparation of 2-methyl-5-(oxiran-2-yl)pyridine

The title compound was prepared by following general procedure 3. DMSO(4 mL) was added to NaH 60% dispersion in oil (0.314 g, 7.8 mmol, 1.3equiv.) and heated to 65° C. for 1 h. THF (10 mL) was added at the sametemperature and heated for another 10 min. After 10 min., the reactionmixture was cooled to 0° C. Trimethylsulfonium iodide (1.2 g, 5.9 mmol,1 equiv.) was added and stirred for 10 min. and then a solution of6-methylnicotinaldehyde (0.720 g, 5.9 mmol, 1 equiv.) in THF was addeddropwise. After complete addition, the reaction mixture was stirred atRT for 2 h, the product was detected by LCMS. The reaction mixture waspoured into ice water and the product was extracted in diethyl ether(4×50 mL), dried over Na₂SO₄ and concentrated at 25° C. to get the crudeproduct 2-methyl-5-(oxiran-2-yl)pyridine (1.1 g crude).

Example 16 Preparation of 2-(4-fluorophenyl)-2-methyloxirane

The title compound was prepared by following general procedure 3. To asolution of trimethylsulfonium iodide (3.5 g, 17.15 mmol, 1.2 equiv.) inDMSO (30 mL) was added sodium hydride 50%-55% dispersion in oil (0.97 g,22.2 mmol, 1.5 equiv.) portionwise over 5 min. and stirred for 1 h atRT. A solution of 1-(4-fluorophenyl)ethanone (2 g, 14.47 mmol, 1 equiv.)in DMSO (10 mL) was added to the reaction mixture dropwise over 20 min.and stirred at RT for 4 h. The progress of the reaction was checked byTLC and the reaction mixture was poured in 100 mL water and extractedwith ethyl acetate (3×100 mL). The combined organic extracts were washedwith water (2×150 mL), followed by brine. The organic layer was driedover sodium sulfate and evaporated to dryness to yield a brown oil (2.2g). ¹H NMR (d6-acetone) was consistent with the structure. Product R_(f)0.8 (ethyl acetate:hexane 10:90)

Example 17 Preparation of 2-p-tolyloxirane

The title compound was prepared by following general procedure 3. To asolution of trimethylsulfonium iodide (10.28 g, 50.37 mmol, 1.2 equiv.)in DMSO (70 mL) was added sodium hydride 60% dispersion in oil (2.82 g,70.5 mmol, 1.7 equiv.) portionwise over 5 min. and stirred for 1 h atRT. A solution of 4-methylbenzaldehyde (5.0 g, 42.0 mmol, 1 equiv.) inDMSO (25 mL) was added to the reaction mixture dropwise over 20 min. Itwas stirred at RT for 4 h. The reaction mixture was checked by TLC andthe reaction mixture was poured in water (150 mL) and extracted withethyl acetate. The combined organic extract was washed with water andbrine and dried over anhydrous sodium sulfate and evaporated to drynessto afford 2-p-tolyloxirane (5.2 g).

Example 18 Preparation of 3-(oxiran-2-yl)pyridine

The title compound was prepared by following general procedure 3. Sodiumhydride 50% dispersion in oil (1.64 g, 34.2 mmol, 1.8 equiv.) was takeninto DMSO (12 mL) and heated at 65° C. for 1 h. THF (36 mL) was added atthe same temperature and heated for 10 min. The reaction mixture wascooled to 0° C. and trimethylsulfonium iodide (3.81 g, 18.6 mmol, 1equiv.) was added, followed by nicotinaldehyde (2 g, 18.6 mmol, 1equiv.) and stirred at RT for 1 h. The reaction was monitored by TLC andLCMS. After completion of the reaction, the reaction mixture was pouredin ice and extracted with diethyl ether, dried over anhydrous sodiumsulfate and evaporated under reduced pressure to afford3-(oxiran-2-yl)pyridine (1 g).

Example 19 Preparation of 2-(2,4,6-trifluorophenyl)-2-methyloxirane

The title compound was prepared by following general procedure 3. DMSOwas added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was addedat the same temperature and heated for another 10 min. After 10 min.,the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1equiv.) was added and stirred for 10 min. after which the solution of1-(2,4,6-trifluorophenyl)ethanone (1 equiv.) in THF was added dropwise.After completion of this addition, the reaction mixture was stirred atRT for 2 h. The product was detected by LCMS and the reaction mixturewas poured into ice water, extracted with diethyl ether (4×50 mL), driedover Na₂SO₄ and concentrated at 25° C. to obtain the product.

Example 20 Preparation of 2-(2,4-dichlorophenyl)-2-methyloxirane

The title compound was prepared by following general procedure 3. DMSOwas added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was addedat the same temperature and heated for another 10 min. After 10 min.,the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1equiv.) was added and the reaction mixture was stirred for 10 min. afterwhich the solution of 1-(2,4-dichlorophenyl)ethanone (1 equiv.) in THFwas added dropwise. After complete addition, the reaction mixture wasstirred at RT for 2 h. The product was detected by LCMS and the reactionmixture was poured into ice water, extracted in diethyl ether (4×50 mL),dried over Na₂SO₄ and concentrated at 25° C. to obtain the product.

Example 21 Preparation of 2-(2,4-difluorophenyl)-2-methyloxirane

The title compound was prepared by following general procedure 3. DMSOwas added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was addedat the same temperature and heated for another 10 min. After 10 min.,the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1equiv.) was added and stirred for 10 min. after which the solution of1-(2,4-difluorophenyl)ethanone (1 equiv.) in THF was added dropwise.After complete addition, the reaction mixture was stirred at RT for 2 h.The product was detected by LCMS and the reaction mixture was pouredinto ice water, extracted in diethyl ether (4×50 mL), dried over Na₂SO₄and concentrated at 25° C. to obtain the product.

Example 22 Preparation of 2-(3,4-dichlorophenyl)-2-methyloxirane

The title compound was prepared by following general procedure 3. DMSOwas added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was addedat the same temperature and heated for another 10 min. After 10 min.,the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1equiv.) was added and stirred for 10 min. after which the solution of1-(3,4-dichlorophenyl)ethanone (1 equiv.) in THF was added dropwise.After complete addition, the reaction mixture was stirred at RT for 2 h.The product was detected by LCMS and the reaction mixture was pouredinto ice water, extracted in diethyl ether (4×50 mL), dried over Na₂SO₄and concentrated at 25° C. to obtain the product.

Example 23 Preparation of 2-(3,4-difluorophenyl)-2-methyloxirane

The title compound was prepared by following general procedure 3. DMSOwas added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was addedat the same temperature and heated for another 10 min. After 10 min.,the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1equiv.) was added and stirred for 10 min. after which the solution of1-(3,4-difluorophenyl)ethanone (1 equiv.) in THF was added dropwise.After complete addition, the reaction mixture was stirred at RT for 2 h.The product was detected by LCMS and the reaction mixture was pouredinto ice water, extracted in diethyl ether (4×50 mL), dried over Na₂SO₄and concentrated at 25° C. to obtain the product.

Example 24 Preparation of 2-(3-chloro-4-fluorophenyl)-2-methyloxirane

The title compound was prepared by following general procedure 3. DMSOwas added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was addedat the same temperature and heated for another 10 min. After 10 min.,the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1equiv.) was added and stirred for 10 min. after which the solution of1-(3-chloro-4-fluorophenyl)ethanone (1 equiv.) in THF was addeddropwise. After complete addition, the reaction mixture was stirred atRT for 2 h. The product was detected by LCMS and the reaction mixturewas poured into ice water, extracted in diethyl ether (4×50 mL), driedover Na₂SO₄ and concentrated at 25° C. to obtain the product.

Example 25 Preparation of 2-(3-fluoro-4-methoxyphenyl)-2-methyloxirane

The title compound was prepared by following general procedure 3. DMSOwas added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was addedat the same temperature and heated for another 10 min. After 10 min.,the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1equiv.) was added and stirred for 10 min. after which the solution of1-(3-fluoro-4-methoxyphenyl)ethanone (1 equiv.) in THF was addeddropwise. After complete addition, the reaction mixture was stirred atRT for 2 h. The product was detected by LCMS, the reaction mixture waspoured into ice water, extracted in diethyl ether (4×50 mL), dried overNa₂SO₄ and concentrated at 25° C. to obtain the product.

Example 26 Preparation of 2-(3-fluoro-4-methoxyphenyl)oxirane

The title compound was prepared by following general procedure 3. DMSOwas added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was addedat the same temperature and heated for another 10 min. After 10 min.,the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1equiv.) was added and stirred for 10 min. after which the solution of3-fluoro-4-methoxybenzaldehyde (1 equiv.) in THF was added dropwise.After complete addition, the reaction mixture was stirred at RT for 2 h.The product was detected by LCMS and the reaction mixture was pouredinto ice water, extracted in diethyl ether (4×50 mL), dried over Na₂SO₄and concentrated at 25° C. to obtain the product.

Example 27 Preparation of 2-(4-chloro-3-fluorophenyl)-2-methyloxirane

The title compound was prepared by following general procedure 3. DMSOwas added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was addedat the same temperature and heated for another 10 min. After 10 min.,the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1equiv.) was added and stirred for 10 min. after which the solution of1-(4-chloro-3-fluorophenyl)ethanone (1 equiv.) in THF was addeddropwise. After complete addition, the reaction mixture was stirred atRT for 2 h. The product was detected by LCMS and the reaction mixturewas poured into ice water, extracted in diethyl ether (4×50 mL), driedover Na₂SO₄ and concentrated at 25° C. to obtain the product.

Example 28 Preparation of 2-(4-chlorophenyl)-2-methyloxirane

The title compound was prepared by following general procedure 3. DMSOwas added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was addedat the same temperature and heated for another 10 min. After 10 min.,the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1equiv.) was added and stirred for 10 min. after which the solution of1-(4-chlorophenyl)ethanone (1 equiv.) in THF was added dropwise. Aftercomplete addition, the reaction mixture was stirred at RT for 2 h. Theproduct was detected by LCMS and the reaction mixture was poured intoice water, extracted in diethyl ether (4×50 mL), dried over Na₂SO₄ andconcentrated at 25° C. to obtain the product.

Example 29 Preparation of 2-(4-fluorophenyl)-2,3-dimethyloxirane

The title compound was prepared by following general procedure 3. DMSOwas added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was addedat the same temperature and heated for another 10 min. After 10 min.,the reaction mixture was cooled to 0° C. Triethylsulfonium iodide (1equiv.) was added and stirred for 10 min. after which the solution of1-(4-fluorophenyl)ethanone (1 equiv.) in THF was added dropwise. Aftercomplete addition, the reaction mixture was stirred at RT for 2 h. Theproduct was detected by LCMS and the reaction mixture was poured intoice water, extracted in diethyl ether (4×50 mL), dried over Na₂SO₄ andconcentrated at 25° C. to obtain the product.

Example 30 Preparation of 2-(4-methoxyphenyl)-2-methyloxirane

The title compound was prepared by following general procedure 3. DMSOwas added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was addedat the same temperature and heated for another 10 min. After 10 min.,the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1equiv.) was added and stirred for 10 min. after which the solution of1-(4-methoxyphenyl)ethanone (1 equiv.) in THF was added dropwise. Aftercomplete addition, the reaction mixture was stirred at RT for 2 h. Theproduct was detected by LCMS and the reaction mixture was poured intoice water, extracted in diethyl ether (4×50 mL), dried over Na₂SO₄ andconcentrated at 25° C. to obtain the product.

Example 31 Preparation of 2-(trifluoromethyl)-2-(4-fluorophenyl)oxirane

The title compound was prepared by following general procedure 3. DMSOwas added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was addedat the same temperature and heated for another 10 min. After 10 min.,the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1equiv.) was added and stirred for 10 min. after which the solution of2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (1 equiv.) in THF was addeddropwise. After complete addition, the reaction mixture was stirred atRT for 2 h. The product was detected by LCMS and the reaction mixturewas poured into ice water, extracted in diethyl ether (4×50 mL), driedover Na₂SO₄ and concentrated at 25° C. to obtain the product.

Example 32 Preparation of2-(trifluoromethyl)-5-(2-methyloxiran-2-yl)pyridine

The title compound was prepared by following general procedure 3. DMSOwas added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was addedat the same temperature and heated for another 10 min. After 10 min.,the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1equiv.) was added and stirred for 10 min. after which the solution of1-(6-(trifluoromethyl)pyridin-3-yl)ethanone (1 equiv.) in THF was addeddropwise. After complete addition, the reaction mixture was stirred atRT for 2 h. The product was detected by LCMS and the reaction mixturewas poured into ice water, extracted in diethyl ether (4×50 mL), driedover Na₂SO₄ and concentrated at 25° C. to obtain the product.

Example 33 Preparation of 2-(trifluoromethyl)-5-(oxiran-2-yl)pyridine

The title compound was prepared by following general procedure 3. DMSOwas added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was addedat the same temperature and heated for another 10 min. After 10 min.,the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1equiv.) was added and stirred for 10 min. after which the solution of6-(trifluoromethyl)pyridine-3-carbaldehyde (1 equiv.) in THF was addeddropwise. After complete addition, the reaction mixture was stirred atRT for 2 h. The product was detected by LCMS and the reaction mixturewas poured into ice water, extracted in diethyl ether (4×50 mL), driedover Na₂SO₄ and concentrated at 25° C. to obtain the product.

Example 34 Preparation of 2-cyclopropyl-2-(4-fluorophenyl)oxirane

The title compound was prepared by following general procedure 3. DMSOwas added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was addedat the same temperature and heated for another 10 min. After 10 min.,the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1equiv.) was added and stirred for 10 min. after which the solution ofcyclopropyl (4-fluorophenyl)methanone (1 equiv.) in THF was addeddropwise. After complete addition, the reaction mixture was stirred atRT for 2 h. The product was detected by LCMS and the reaction mixturewas poured into ice water, extracted in diethyl ether (4×50 mL), driedover Na₂SO₄ and concentrated at 25° C. to obtain the product.

Example 35 Preparation of 2-ethyl-2-(4-fluorophenyl)oxirane

The title compound was prepared by following general procedure 3. DMSOwas added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was addedat the same temperature and heated for another 10 min. After 10 min.,the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1equiv.) was added and stirred for 10 min. after which the solution of1-(4-fluorophenyl)propan-1-one (1 equiv.) in THF was added dropwise.After complete addition, the reaction mixture was stirred at RT for 2 h.The product was detected by LCMS and the reaction mixture was pouredinto ice water, extracted in diethyl ether (4×50 mL), dried over Na₂SO₄and concentrated at 25° C. to obtain the product.

Example 36 Preparation of 2-methyl-2-phenyloxirane

The title compound was prepared by following general procedure 3. DMSOwas added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was addedat the same temperature and heated for another 10 min. After 10 min.,the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1equiv.) was added and stirred for 10 min. after which the solution ofacetophenone (1 equiv.) in THF was added dropwise. After completeaddition, the reaction mixture was stirred at RT for 2 h. The productwas detected by LCMS and the reaction mixture was poured into ice water,extracted in diethyl ether (4×50 mL), dried over Na₂SO₄ and concentratedat 25° C. to obtain the product.

Example 37 Preparation of 2-methyl-5-(2-methyloxiran-2-yl)pyridine

The title compound was prepared by following general procedure 3. DMSOwas added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was addedat the same temperature and heated for another 10 min. After 10 min.,the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1equiv.) was added and stirred for 10 min. after which the solution of1-(6-methylpyridin-3-yl)ethanone (1 equiv.) in THF was added dropwise.After complete addition, the reaction mixture was stirred at RT for 2 h.The product was detected by LCMS and the reaction mixture was pouredinto ice water, extracted in diethyl ether (4×50 mL), dried over Na₂SO₄and concentrated at 25° C. to obtain the product.

Example 38 Preparation of 2-methyl-5-(2-methyloxiran-2-yl)pyrimidine

The title compound was prepared by following general procedure 3. DMSOwas added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was addedat the same temperature and heated for another 10 min. After 10 min.,the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1equiv.) was added and stirred for 10 min. after which the solution of1-(2-methylpyrimidin-5-yl)ethanone (1 equiv.) in THF was added dropwise.After complete addition, the reaction mixture was stirred at RT for 2 h.The product was detected by LCMS and the reaction mixture was pouredinto ice water, extracted in diethyl ether (4×50 mL), dried over Na₂SO₄and concentrated at 25° C. to obtain the product.

Example 39 Preparation of9-chloro-6-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole(Compound No. 1)

The title compound was prepared by following general procedure 4. Amixture of 9-chloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole(117 mg, 0.5 mmol) 2-trifluoromethyl-5-vinylpyridine (95 mg, 0.55 mmol,1.1 equiv.) and KOH (crushed, 98 mg, 1.75 mmol, 3.5 equiv.) in NMP (0.3mL) was stirred and heated at 50° C. for 3 h. The reaction mixture wascooled to RT and diluted by adding ice and satd. aqueous NaCl. Theaqueous was extracted with ethyl acetate and organic layer was washedwith brine, dried over anhydrous sodium sulfate and concentrated undervacuum to obtain crude product as an orange oil (153 mg). The crudeproduct was purified by flash chromatography on silica gel (6 g, 40-63micron, 230-400 mesh) eluting with ethyl acetate followed by ethylacetate: ethanol: aqueous ammonia (90:10:1) to obtain 80 mg (39% yield)of9-chloro-6-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indoleas free base. The free base was converted into its HCl salt by treatmentwith HCl-ether.

Example 40 Preparation of9-chloro-3-methyl-6-(2-(5-methylpyridin-3-yl)ethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 3)

The title compound was prepared by following general procedure 4.9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg,0.85 mmol), tetra n-butyl ammonium chloride (11 mg, 0.043 mmol),3-methyl-5-vinylpyridine (121 mg, 1.02 mmol) were taken into 50% NaOH (6mL) and the reaction mixture was heated overnight at 90° C. The reactionwas monitored by TLC. After completion of reaction, the reaction mixturewas extracted with ethyl acetate and water, the organic layer wasseparated, dried over Na₂SO₄, and concentrated under reduced pressure.The crude compound was purified by preparative TLC to obtain 9 mg of9-chloro-3-methyl-6-(2-(5-methylpyridin-3-yl)ethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,isolated as its oxalate salt. 1HNMR (CD3OD, Oxalate salt) δ (ppm): 8.40(s, 1H), 8.0 (s, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.18 (d, 1H), 7.0 (d,1H), 4.40 (t, 2H), 3.70 (t, 2H), 3.30 (s, 3H), 3.20 (m, 5H), 3.0 (s,3H), 2.38 (s, 3H).

Example 41 Preparation of6-(2-(5-chloropyridin-3-yl)ethyl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole(Compound No. 4)

The title compound was prepared by following general procedure 4.3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46mmol), tetra n-butyl ammonium chloride (6 mg, 0.023 mmol),3-chloro-5-vinylpyridine (77 mg, 0.55 mmol) were taken into 50% NaOH (3mL). The reaction mixture was heated overnight at 110° C. The reactionmixture was extracted with ethyl acetate and organic layer was driedover Na₂SO₄, and concentrated under reduced pressure to obtain 150 mg of6-(2-(5-chloropyridin-3-yl)ethyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoleas the TFA salt after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).

Example 42 Preparation of9-chloro-1,2,3,4,5,6-hexahydro-3-methyl-6-(2-(pyridin-4-yl)ethyl)azepino[4,5-b]indole(Compound No. 5)

The title compound was prepared by following general procedure 4.9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg,0.42 mmol), tetra n-butyl ammonium chloride (6 mg, 0.025 mmol),4-vinylpyridine (53 mg, 0.51 mmol) were taken into 50% NaOH (3 mL). Thereaction mixture was heated overnight at 110° C. The reaction wasmonitored by TLC. After completion of reaction, the reaction mixture wasextracted with ethyl acetate and water, the organic layer was dried overNa₂SO₄, and concentrated under reduced pressure to obtain 40 mg of9-chloro-3-methyl-6-(2-(pyridin-4-yl)ethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoleas the TFA salt after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).

Example 43 Preparation of1,2,3,4,5,6-hexahydro-3,9-dimethyl-6-(2-(pyridin-4-yl)ethyl)azepino[4,5-b]indole(Compound No. 6)

The title compound was prepared by following general procedure 4.3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46mmol), tetra n-butyl ammonium chloride (6 mg, 0.023 mmol),4-vinylpyridine (58 mg, 0.55 mmol) were taken into 50% NaOH (3 mL). Thereaction mixture was heated overnight at 110° C. The reaction mixturewas extracted with ethyl acetate and organic layer was dried overNa₂SO₄, and concentrated under reduced pressure to obtain 100 mg of3,9-dimethyl-6-(2-(pyridin-4-yl)ethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoleas the TFA salt after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).

Example 44 Preparation of9-chloro-1,2,3,4,5,6-hexahydro-3-methyl-6-(2-(pyridin-2-yl)ethyl)azepino[4,5-b]indole(Compound No. 8)

The title compound was prepared by following general procedure 4. To asolution of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(150 mg, 0.6 mmol) in 50% aq. NaOH solution (7 mL), tetra n-butylammonium chloride (9 mg, 0.03 mmol) was added followed by2-vinylpyridine (74 mg, 0.7 mmol) The reaction mixture was heated at 80°C. for 14 h. After completion of reaction, the reaction mixture wasdiluted with water, extracted with ethyl acetate; the organic layer wasdried over Na₂SO₄, and concentrated under reduced pressure. The crudeproduct was purified by reverse phase chromatography to afford 80 mg of9-chloro-3-methyl-6-(2-(pyridin-2-yl)ethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoleas the TFA salt.

Example 45 Preparation of1,2,3,4,5,6-hexahydro-3,9-dimethyl-6-(2-(pyridin-2-yl)ethyl)azepino[4,5-b]indole(Compound No. 9)

The title compound was prepared by following general procedure 4. To asolution of 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (150mg, 0.7 mmol) in 50% aq. NaOH solution (7 mL) tetra n-butyl ammoniumchloride (9 mg, 0.03 mmol) followed by 2-vinylpyridine (80 mg, 0.77mmol) was added and the reaction mixture was heated at 80° C. for 14 h.After completion of reaction, the reaction mixture was diluted withwater, extracted with ethyl acetate; the organic layer was dried overNa₂SO₄, and concentrated under reduced pressure. The crude product waspurified by reverse phase chromatography to afford 80 mg of3,9-dimethyl-6-(2-(pyridin-2-yl)ethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoleas the TFA salt.

Example 46 Preparation of9-chloro-6-(2-(5-chloropyridin-3-yl)ethyl)-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole(Compound No. 10)

The title compound was prepared by following general procedure 4. To asolution of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(100 mg, 0.42 mmol) in 50% aq. NaOH solution (5 mL) tetra n-butylammonium chloride (9 mg, 0.03 mmol) followed by 3-chloro-5-vinylpyridine(65 mg, 0.47 mmol) was added. The reaction mixture was heated at 60° C.for 8 h. After completion of reaction, the reaction mixture was dilutedwith water, extracted with ethyl acetate; the organic layer was driedover Na₂SO₄, and concentrated under reduced pressure. The crude productwas purified by reverse phase chromatography to afford 5 mg of9-chloro-6-(2-(5-chloropyridin-3-yl)ethyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoleas the TFA salt.

Example 47 Preparation of5-(2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)ethyl)pyridine-2-carboxylicacid (Compound No. 11)

The title compound was prepared by following general procedure 4. To asolution of 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (200mg, 0.93 mmol) in 50% aq. NaOH solution (3 mL) was added, tetra n-butylammonium chloride (12 mg, 0.046 mmol) followed by 5-vinylpicolinic acid(153 mg, 1.0 mmol). The reaction mixture was heated at 90° C. forovernight, and the reaction was monitored by TLC. After completion ofreaction, the reaction mixture was diluted with water, extracted withethyl acetate. The organic layer was separated, dried over Na₂SO₄, andconcentrated under reduced pressure. The crude product was purified byreverse phase chromatography to afford 7 mg of5-(2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl)picolinicacid as the TFA salt.

Example 48 Preparation of6-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole(Compound No. 20)

The title compound was prepared by following general procedure 4. To asolution of 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (150mg, 0.69 mmol) in 50% aq. NaOH solution (3 mL) was added, tetra n-butylammonium chloride (9 mg, 0.034 mmol) followed by2-(trifluoromethyl)-5-vinylpyridine (133 mg, 0.76 mmol). The reactionmixture was heated at 120° C. for 8 h and the reaction was monitored byTLC. After completion of reaction, the reaction mixture was diluted withwater, extracted with ethyl acetate. The organic layer was separated,dried over anhydrous Na₂SO₄, and concentrated under reduced pressure.The crude product was purified by reverse phase chromatography to afford15 mg of3,9-dimethyl-6-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoleas the TFA salt.

Example 49 Preparation of5-(2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)ethyl)pyridine-2-carboxylicacid (Compound No. 21)

The title compound was prepared by following general procedure 4. To asolution of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(200 mg, 0.85 mmol) in 50% aq. NaOH solution (3 mL) was added, tetran-butyl ammonium chloride (11 mg, 0.042 mmol) followed by5-vinylpicolinic acid (140 mg, 0.94 mmol). The reaction mixture washeated at 90° C. for overnight and was monitored by TLC. Aftercompletion of reaction, the reaction mixture was diluted with water,extracted with ethyl acetate. The organic layer was separated, driedover anhydrous Na₂SO₄, and concentrated under reduced pressure. Thecrude product was purified by reverse phase chromatography to afford 8mg of5-(2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl)picolinicacid as the TFA salt.

Example 50 Preparation of6-(4-chlorophenethyl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole(Compound No. 28)

The title compound was prepared by following general procedure 4.6-(4-Chlorophenethyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.214 g, 1 mmol)along with tetrabutylammonium chloride (0.138 g, 0.0005 mmol) were takeninto 50% aq. NaOH solution (5 mL) and stirred for 5 min. at RT,1-(2-bromoethyl)-4-chlorobenzene (0.219 g, 1 mmol) was added and stirredfor 5 min. at RT and then the reaction mixture was heated at 110° C. forovernight. The product detected by LCMS, extracted in ethyl acetate,dried over anhydrous sodium sulfate, concentrated and purified byreverse phase chromatography to get the pure compound6-(4-chlorophenethyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.

Example 51 Preparation of6-(2-chlorophenethyl)-9-chloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole(Compound No. 29)

The title compound was prepared by following general procedure 4.9-Chloro-6-(2-chlorophenethyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.234 g, 1mmol) along with tetrabutylammonium chloride (0.026 g, 0.094 mmol) weretaken into 50% aq. NaOH solution (4 mL) and stirred for 15 min. at RT,1-(2-bromoethyl)-2-chlorobenzene (0.878 g, 4 mmol) was added and stirredfor 10 min. at RT and then the reaction mixture was heated at 100° C.for overnight. Product detected by LCMS. The product was extracted inethyl acetate, dried over anhydrous sodium sulfate, concentrated andpurified by reverse phase chromatography to get pure compound9-chloro-6-(2-chlorophenethyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole as the TFA salt (70 mg)

Example 52 Preparation of6-(4-chlorophenethyl)-9-chloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole(Compound No. 30)

The title compound was prepared by following general procedure 4.9-Chloro-6-(4-chlorophenethyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.234 g, 1mmol) along with tetrabutylammonium chloride (0.026 g, 0.094 mmol) weretaken into 50% aq. NaOH solution (4 mL) and stirred for 15 m in. at RT,1-(2-bromoethyl)-4-chlorobenzene (0.878 g, 4 mmol) was added and stirredfor 10 min. at RT and the reaction mixture was heated at 100° C. forovernight. The product detected by LCMS, extracted in ethyl acetate,dried over anhydrous sodium sulfate, concentrated and purified byreverse phase chromatography to get pure compound9-chloro-6-(4-chlorophenethyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole as the TFA salt (50 mg)

Example 53 Preparation of9-chloro-3-methyl-6-(4-methylphenethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 46)

The title compound was prepared by following general procedure 4. TBACl(138 mg, 0.5 mmol) was taken into 50% NaOH (5 mL), and to it was added9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepinol[4,5-b]indole (234 mg,1.0 mmol), stirred for 5 min. at RT, and added1-(2-bromoethyl)-4-methylbenzene (199 mg, 1.0 mmol), the reaction wasthen stirred at 110° C. for 12 h. The completion of reaction was checkedby LCMS. Water was added and the mixture extracted by DCM which wasdried over sodium sulfate and concentrated under vacuum. The crude soobtained was purified by reverse phase chromatography to get pureproduct.

Example 54 Preparation of9-chloro-1,2,3,4,5,6-hexahydro-3-methyl-6-phenethylazepino[4,5-b]indole(Compound No. 56)

The title compound was prepared by following general procedure 4. TBACl(59 mg, 0.213 mmol) was taken into 50% NaOH (5 mL), to it added9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepinol[4,5-b]indole (100 mg,0.426 mmol), stirred for 5 min. at RT and added (2-bromoethyl)benzene(78 mg, 0.426 mmol) the reaction was stirred at 100° C. for 12 h. Thecompletion of reaction was checked by LCMS. Water was added and themixture extracted with DCM which was dried over sodium sulfate andconcentrated under vacuum. The crude so obtained was purified by reversephase chromatography. The pure compound so obtained was made free baseand converted to oxalate salt in THF.

Example 55 Preparation of6-(2-fluorophenethyl)-9-chloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole(Compound No. 61)

The title compound was prepared by following general procedure 4.9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1.0mmol) was taken with copper iodide (19 mg, 0.1 mmol), L-proline (23 mg,0.2 mmol), potassium phosphate tribasic (426 mg, 2.0 mmol) and then1-(2-bromoethyl)-2-fluorobenzene (203 mg, 1 mmol) in DMF. The reactionmixture was stirred at 90° C. under argon atmosphere for 12 h andmonitored by LCMS. After completion of the reaction, water was added andextracted with ethyl acetate. The ethyl acetate layer was washed withwater, dried over sodium sulfate and concentrated under vacuum. Thecrude product was purified by column chromatography (silica gel 100-200mesh) (gradient 5% MeOH:DCM). The pure product was converted to itsoxalate salt using oxalic acid and THF.

Example 56 Preparation of1,2,3,4,5,6-hexahydro-3,9-dimethyl-6-phenethylazepino[4,5-b]indole(Compound No. 62)

The title compound was prepared by following general procedure 4.3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1.0mmol) was taken with copper iodide (19 mg, 0.1 mmol), L-proline (23 mg,0.2 mmol), potassium phosphate tribasic (426 mg, 2.0 mmol) and(2-bromoethyl)benzene (185 mg, 1 mmol) and DMF was added, the reactionwas stirred at 90° C. under argon atmosphere for 12 h. The reaction wasmonitored by LCMS. After completion of the reaction, water was added andextracted with ethyl acetate. The organic layer was washed with water,dried over sodium sulfate and concentrated under vacuum. The crude soobtained was purified by column chromatography (silica gel 100-200 mesh)(gradient 5% MeOH:DCM). The pure product was converted to oxalate saltusing oxalic acid and THF.

Example 57 Preparation of6-(2-fluorophenethyl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole(Compound No. 63)

The title compound was prepared by following general procedure 4.Tetrabutylammonium chloride (138 mg, 0.0005 mmol) was taken into 50%NaOH (10 mL) 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214mg, 1.0 mmol) was added and stirred for 5 min. at RT.1-(2-Bromoethyl)-2-fluorobenzene (203 mg, 1 mmol) was added, thereaction was stirred at 100° C. for 12 h. The completion of reaction waschecked by LCMS. Water was added to the reaction mixture and extractedwith DCM which was dried over sodium sulfate and concentrated undervacuum. The crude product was purified by reverse phase chromatographyto afford the title compound.

Example 58 Preparation of6-(2-chlorophenethyl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole(Compound No. 69)

The title compound was prepared by following general procedure 4.3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1.0mmol) was taken with copper iodide (19 mg, 0.1 mmol), L-praline (23 mg,0.2 mmol), potassium phosphate tribasic (426 mg, 2.0 mmol),1-(2-bromoethyl)-2-chlorobenzene (219 mg, 1.0 mmol) and DMF was added,the reaction was stirred at 90° C. under argon atmosphere for 12 h andmonitored by LCMS. After completion of the reaction water was added andextracted with ethyl acetate. The organic layer was washed with water,dried over sodium sulfate and concentrated under vacuum. The crudeproduct was purified by reverse phase chromatography to afford 50 mg ofthe title compound (10.7%).

Example 59 Preparation ofN-cyclohexyl-3-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-N-methylpropanamide(Compound No. 81)

The title compound was prepared by following general procedure 8. Sodiumhydride (0.027 g, 0.69 mmol) washed with hexane for removal of oil anddried under vacuum. Then the sodium hydride was taken into THF. To thissolution 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.1 g,0.46 mmol) in THF was added dropwise at 0° C. Then the reaction mixturewas stirred for 0.5 h. The solution of N-cyclohexyl-N-methylacrylamide(0.115 g, 0.93 mmol) in THF was added dropwise into the reactionmixture. The reaction mixture was stirred at RT for 2 h and monitored byTLC. After completion of reaction, the reaction mixture was quenchedwith ice-water. The crude compound was purified by preparative TLC. Thepure compound was stirred in ethanolic HCl to give 6 mg HCl salt ofN-cyclohexyl-3-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-methylpropanamide.

Example 60 Preparation of2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(6-methylpyridin-3-yl)ethanol(Compound No. 7)

The title compound was prepared by following general procedure 5.9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1mmol) was dissolved in DMF (2 mL). To a solution of sodium hydride (50%)(100 mg, 2.2 mmol) was added in portions at RT and stirred at RT for 10min. A solution of 2-methyl-5-(oxiran-2-yl)pyridine (270 mg, 2 mmol) inDMF (1 mL) was added dropwise for 10 min. and stirred for overnight atRT. The product was detected by LCMS, the reaction mixture was quenchedwith methanol and concentrated to dryness. Water was added to theresidue and product was extracted in ethyl acetate (3×50 mL). Theorganic layer was dried over anhydrous sodium sulfate and evaporatedunder reduced pressure. The crude product was purified by reverse phasechromatography to get2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(6-methylpyridin-3-yl)ethanolas the TFA salt (195 mg, 40.37%). 1HNMR (DMSO-d6, TFA salt) δ (ppm):8.40 (s, 1H), 7.90 (s, 1H), 7.60 (s, 1H), 7.40 (m, 2H), 7.0 (m, 1H),5.80 (m, 1H), 4.90 (m, 1H), 4.30 (m, 1H), 3.60 (m, 4H), 3.20 (m, 4H),3.0 (m, 4H), 2.80 (s, 3H).

Example 61 Preparation of1-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-2-(4-chlorophenyl)propan-2-ol(Compound No. 12)

The title compound was prepared by following general procedure 5. To astirred suspension of sodium hydride (61 mg, 0.254 mmol) in 5 mL of DMF,9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.2 g,0.852 mmol) was added and stirred at RT for 5 min.2-(4-Chlorophenyl)-2-methyloxirane (214 mg, 1.27 mmol) was added slowlydropwise and stirred at RT for 14 h. The reaction was monitored by TLCand LCMS. After completion of the reaction, water was added, extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate, evaporated under reduced pressure and purified by reverse phasechromatography to afford 150 mg of(1-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(4-chlorophenyl)propan-2-ol)as the TFA salt.

Example 62 Preparation of1-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-2-(4-fluorophenyl)propan-2-ol(Compound No. 13)

The title compound was prepared by following general procedure 5. To astirred suspension of sodium hydride (61 mg, 0.254 mmol) in 5 mL of DMF,9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.2 g,0.852 mmol) was added and stirred at RT for 5 min.2-(4-Fluorophenyl)-2-methyloxirane (194 mg, 1.27 mmol) was added slowlydropwise and stirred at RT for 14 h. The reaction was monitored by TLCand LCMS. After completion of the reaction, water was added, extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate, evaporated under reduced pressure and purified by reverse phasechromatography to afford 150 mg of(1-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(4-fluorophenyl)propan-2-ol)as the TFA salt. ¹H NMR (DMSO-d6, TFA salt) δ (ppm): 7.40 (s, 1H),7.30-7.18 (m, 3H), 7.0-6.80 (m, 3H), 4.40-4.25 (d, 2H), 4.25-4.15 (d,2H), 3.40-3.20 (d, 2H), 3.20-3.00 (m, 4H), 2.90 (s, 3H), 1.50 (s, 3H).

Example 63 Preparation of2-(4-fluorophenyl)-1-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)propan-2-ol(Compound No. 14)

The title compound was prepared by following general procedure 5. To astirred suspension of sodium hydride (67 mg, 0.28 mmol) in 5 mL of DMF,3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.2 g, 0.934mmol) was added and stirred at RT for 5 min.2-(4-Fluorophenyl)-2-methyloxirane (212 mg, 1.39 mmol) was added slowlydropwise and stirred at RT for 14 h. The reaction was monitored by TLCand LCMS. After completion of the reaction, water was added, extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate, evaporated under reduced pressure and purified by columnchromatography using 10% methanol-DCM. The freebase (30 mg, 0.082 mmol)was dissolved in THF (1.0 mL) and oxalic acid (10 mg, 0.082 mmol) in THF(1.0 mL) was added slowly, the mixture was stirred at RT for 20 min. andthe formed solid was filtered, washed with ether and dried to afford theproduct as oxalate salt (15 mg, brown solid).

Example 64 Preparation of2-(4-chlorophenyl)-1-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)propan-2-ol(Compound No. 15)

The title compound was prepared by following general procedure 5. To astirred suspension of sodium hydride (67 mg, 0.28 mmol) in 5 mL of DMF,3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.2 g, 0.934mmol) was added and stirred at RT for 5 min.2-(4-Chlorophenyl)-2-methyloxirane (235 mg, 1.4 mmol) was added slowlydropwise and stirred at RT for 14 h. The reaction was monitored by TLCand LCMS. After completion of the reaction, water was added, extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate, evaporated under reduced pressure and purified by columnchromatography using 10% methanol-DCM. The freebase (30 mg, 0.078 mmol)was dissolved in THF (1.0 mL) and oxalic acid (9.8 mg, 0.078 mmol) inTHF (1.0 mL) was added slowly, the mixture was stirred at RT for 20 min.and the formed solid was filtered, washed with ether and dried to affordproduct as oxalate salt.

Example 65 Preparation of2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(4-chlorophenyl)ethanol(Compound No. 16)

The title compound was prepared by following general procedure 5. To astirred suspension of sodium hydride (153 mg, 6.37 mmol) in 5 mL of DMF,9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.5 g, 2.13mmol) was added and stirred at RT for 10 min. 2-(4-Chlorophenyl)oxirane(493 mg, 3.19 mmol) in DMF (5 mL) was added slowly dropwise and stirredat RT for 14 h. The reaction was monitored by TLC and LCMS. Aftercompletion of the reaction, the reaction mixture quenched with icewater, extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate, evaporated under reduced pressure and purifiedby reverse phase chromatography to afford2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-chlorophenyl)ethanolas the TFA salt (110 mg).

Example 66 Preparation of1-(4-chlorophenyl)-2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)ethanol(Compound No. 17)

The title compound was prepared by following general procedure 5. To astirred suspension of sodium hydride (167 mg, 6.99 mmol) in DMF (5 mL),3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.5 g, 2.33mmol) was added and stirred at RT for 10 min. 2-(4-Chlorophenyl)oxirane(541 mg, 3.504 mmol) in DMF (5 mL) was added slowly dropwise and stirredat RT for 14 h. The reaction was monitored by TLC and LCMS. Aftercompletion of the reaction, the reaction mixture quenched with water,extracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous sodium sulfate, evaporated under reduced pressureand purified by reverse phase chromatography to afford1-(4-chlorophenyl)-2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethanolas the TFA salt (180 mg).

Example 67 Preparation of2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-3-yl)ethanol(Compound No. 18)

The title compound was prepared by following general procedure 5. To astirred suspension of sodium hydride (92 mg, 3.83 mmol) in 5 mL of DMF,9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.3 g, 1.27mmol) was added and stirred at RT for 5 min. 3-(Oxiran-2-yl)pyridine(232 mg, 1.92 mmol) in DMF (5 mL) was added slowly dropwise and stirredat RT for 14 h. The reaction was monitored by TLC and LCMS. Aftercompletion of the reaction, the reaction mixture quenched with icewater, extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous sodium sulfate, evaporated under reducedpressure and purified by reverse phase chromatography to afford 250 mgof2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-3-yl)ethanolas the TFA salt.

Example 68 Preparation of2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-3-yl)ethanol(Compound No. 19)

The title compound was prepared by following general procedure 5. To astirred suspension of sodium hydride (94 mg, 3.92 mmol) in 5 mL of DMF,3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.3 g, 1.40mmol) was added and stirred at RT for 5 min. 3-(Oxiran-2-yl)pyridine(254 mg, 1.54 mmol) in DMF (5 mL) was added slowly dropwise and stirredat RT for 14 h. The reaction was monitored by LCMS. After completion ofthe reaction, the reaction mixture was diluted with water, extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate, evaporated under reduced pressure and purified by reverse phasechromatography to afford 200 mg of2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-3-yl)ethanolas the TFA salt.

Example 69 Preparation of2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-1-(6-methylpyridin-3-yl)ethanol(Compound No. 23)

The title compound was prepared by following general procedure 5.2-(3,9-Dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(6-methylpyridin-3-yl)ethanol3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1 mmol)was taken into DMF (2 mL). To a solution of sodium hydride (50%) (100mg, 2.2 mmol) was in portions at RT and stirred at RT for 10 min. Asolution of 2-methyl-5-(oxiran-2-yl)pyridine (270 mg, 2 mmol) in DMF (1mL) was added dropwise for 10 min. and stirred for overnight at RT. Theproduct was detected by LCMS, the reaction mixture was quenched withmethanol and concentrated to dryness. Water was added to the residue andproduct was extracted in ethyl acetate (3×50 mL). The organic layer wasdried over anhydrous sodium sulfate and evaporated under reducedpressure. The crude product was purified by reverse phase chromatographyto get pure product2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(6-methylpyridin-3-yl)ethanolas the TFA salt (10 mg).

Example 70 Preparation of2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-phenylethanol(Compound No. 24)

The title compound was prepared by following general procedure 5.(2-(9-Chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-phenylethanol.To a solution of9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg,1.27 mmol) in 6.0 mL DMF, sodium hydride (92 mg, 3.834 mmol) was addedslowly portionwise at RT, followed by the addition of 2-phenyloxirane(230 mg, 1.917 mmol) and stirred at RT for 14 h. The reaction mixturewas quenched with water, extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and evaporated under reducedpressure. The crude product was purified using reverse phasechromatography to obtain 150 mg of product as the TFA salt.

Example 71 Preparation of2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-1-phenylethanol(Compound No. 25)

The title compound was prepared by following general procedure 5.(2-(3,9-Dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-phenylethanol).To a solution of 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(300 mg, 1.40 mmol) in 10 mL DMF, sodium hydride (100 mg, 4.203 mmol)was added slowly portionwise at RT, followed by the addition of2-phenyloxirane (252 mg, 2.10 mmol) and stirred at RT for 14 h. LCMSshows the formation of product. The reaction mixture was quenched withwater, extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate and evaporated under reduced pressure. Thecrude product was purified using reverse phase chromatography to obtain250 mg of product as the TFA salt.

Example 72 Preparation of2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-p-tolylethanol(Compound No. 26)

The title compound was prepared by following general procedure 5.(2-(9-Chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-p-tolylethanol).To a solution of9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg,1.27 mmol) in 10 mL DMF, sodium hydride (92 mg, 3.834 mmol) was addedslowly portionwise at RT, followed by the addition of 2-p-tolyloxirane(256 mg, 1.917 mmol) and stirred at RT for 14 h. The reaction mixturewas quenched with water, extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and evaporated under reducedpressure. The crude product was purified using reverse phasechromatography to obtain 230 mg of product as the TFA salt.

Example 73 Preparation of2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-1-p-tolylethanol(Compound No. 27)

The title compound was prepared by following general procedure 5.(2-(3,9-Dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-p-tolylethanol).To a solution of 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(300 mg, 1.40 mmol) in 10 mL DMF, sodium hydride (100 mg, 4.203 mmol)was added slowly portionwise at RT, followed by the addition of2-p-tolyloxirane (281 mg, 2.10 mmol) and stirred at RT for 14 h. LCMSshows the formation of product. The reaction mixture was quenched withwater, extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate and evaporated under reduced pressure. Thecrude product was purified using reverse phase chromatography to obtain85 mg of (Yield: 17.3.0%) title compound as the TFA salt.

Example 74 Preparation of2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluorophenyl)ethanol(Compound No. 40)

The title compound was prepared by following general procedure 5.9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg,1.27 mmol) was taken into DMF (6 mL). To a solution of sodium hydride(50%) (92 mg, 3.83 mmol) was added in portions at RT and stirred at RTfor 10 min. A solution of 2-(2-fluorophenyl)oxirane (264 mg, 1.92 mmol)in DMF (1 mL) was added dropwise for 10 min. and stirred for 14 h at RT.The product was detected by LCMS, the reaction mixture was quenched withice water, extracted in ethyl acetate. The organic layer was dried overanhydrous sodium sulfate and evaporated under reduced pressure. Thecrude product was purified by reverse phase chromatography to get pureproduct2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluorophenyl)ethanolas the TFA salt (240 mg). ¹H NMR (DMSO-d6, TFA salt) δ (ppm): 7.70-7.50(m, 2H), 7.40-7.00 (m, 5H), 5.10-5.00 (t, 1H), 4.40-4.20 (m, 4H),3.40-3.10 (m, 6H), 2.90 (s, 3H).

Example 75 Preparation of1-(2-fluorophenyl)-2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)ethanol(Compound No. 41)

The title compound was prepared by following general procedure 5.3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.40mmol) was taken into DMF (6 mL). To a solution of sodium hydride (50%)(100 mg, 4.22 mmol) was added in portions at RT and stirred at RT for 10min. A solution of 2-(2-fluorophenyl)oxirane (290 mg, 2.11 mmol) in DMF(1 mL) was added dropwise for 10 min. and stirred for 14 h at RT. Thereaction was monitored by TLC and LCMS. The reaction mixture wasquenched with ice water, extracted in ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and evaporated under reducedpressure. The crude product was purified by reverse phase chromatographyto get pure product2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluorophenyl)ethanolas the TFA salt (260 mg). 1HNMR (DMSO-d6, TFA salt) δ (ppm): 7.60 (m,1H), 7.30 (m, 5H), 6.99 (m, 1H), 5.80 (m, 1H), 5.05 (m, 1H), 4.30 (m,2H), 3.80 (m, 4H), 3.35 (m, 4H), 3.0 (s, 3H), 2.40 (s, 3H).

Example 76 Preparation of2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-4-yl)ethanol(Compound No. 42)

The title compound was prepared by following general procedure 5.9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg,1.27 mmol) was taken into DMF (6 mL). To a solution of sodium hydride(50%) (92 mg, 3.83 mmol) was added in portions at RT and stirred at RTfor 10 min. A solution of 4-(oxiran-2-yl)pyridine (232 mg, 1.9 mmol) inDMF (1 mL) was added dropwise for 10 min. and stirred for 14 h at RT.The reaction was monitored by TLC and LCMS. The reaction mixture wasquenched with ice water, extracted in ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and evaporated under reducedpressure. The crude product was purified by reverse phase chromatographyto get pure product2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-4-yl)ethanolas the TFA salt (230 mg). 1HNMR (DMSO-d6, TFA salt) δ (ppm): 8.65 (m,2H), 7.80-7.45 (m, 3H), 7.40 (m, 1H), 7.0 (m, 1H), 6.0 (m, 1H), 4.95 (m,1H), 4.40 (m, 2H), 3.40 (m, 3H), 3.20 (m, 4H), 2.92 (s, 3H).

Example 77 Preparation of2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-4-yl)ethanol(Compound No. 43)

The title compound was prepared by following general procedure 5.3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.40mmol) was taken into DMF (6 mL). To a solution of sodium hydride (50%)(100 mg, 4.22 mmol) was added in portions at RT and stirred at RT for 10min. A solution of 4-(oxiran-2-yl)pyridine (254 mg, 2.11 mmol) in DMF (1mL) was added dropwise for 10 min. and stirred for 14 h at RT. Thereaction was monitored by TLC and LCMS. The reaction mixture wasquenched with ice water, extracted in ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and evaporated under reducedpressure. The crude product was purified by reverse phase chromatographyto get pure product2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-4-yl)ethanolas the TFA salt (250 mg).

Example 78 Preparation of2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(4-methoxyphenyl)ethanol(Compound No. 47)

The title compound was prepared by following general procedure 5.9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg,1.27 mmol) was taken into DMF (8 mL). To a solution of sodium hydride(50%) (92 mg, 3.83 mmol) was added in portions at RT and stirred at RTfor 10 min. A solution of 2-(4-methoxyphenyl)oxirane (287 mg, 1.92 mmol)in DMF (2 mL) was added dropwise for 10 min. and stirred for 14 h at RT.The reaction was monitored by TLC and LCMS. The reaction mixture wasquenched with ice water, extracted in ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and evaporated under reducedpressure. The crude product was purified by reverse phase chromatographyto get pure product2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-methoxyphenyl)ethanolas the TFA salt (150 mg).

Example 79 Preparation of2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-1-(4-methoxyphenyl)ethanol(Compound No. 48)

The title compound was prepared by following general procedure 5.3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.40mmol) was taken into DMF (8 mL). To a solution of sodium hydride (50%)(100 mg, 4.22 mmol) was added in portions at RT and stirred at RT for 10min. A solution of 2-(4-methoxyphenyl)oxirane (315 mg, 2.11 mmol) in DMF(2 mL) was added dropwise for 10 min. and stirred for 14 h at RT. Thereaction was monitored by TLC and LC MS. The reaction mixture wasquenched with ice water, extracted in ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and evaporated under reducedpressure. The crude product was purified by reverse phase chromatographyto get pure product2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-methoxyphenyl)ethanolas the TFA salt (210 mg).

Example 80 Preparation of2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluoro-4-methoxyphenyl)ethanol(Compound No. 49)

The title compound was prepared by following general procedure 5.9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg,1.27 mmol) was taken into DMF (8 mL). To a solution of sodium hydride(50%) (92 mg, 3.83 mmol) was added in portions at RT and stirred at RTfor 10 min. A solution of 2-(2-fluoro-4-methoxyphenyl)oxirane (322 mg,1.92 mmol) in DMF (2 mL) was added dropwise for 10 min. and stirred for14 h at RT. The reaction was monitored by TLC and LCMS. The reactionmixture was quenched with ice water, extracted in ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and evaporatedunder reduced pressure. The crude product was purified by reverse phasechromatography to get pure product2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluoro-4-methoxyphenyl)ethanol as the TFA salt (230 mg).

Example 81 Preparation of1-(2-fluoro-4-methoxyphenyl)-2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)ethanol(Compound No. 50)

The title compound was prepared by following general procedure 5.3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.40mmol) was taken into DMF (8 mL). To a solution of sodium hydride (50%)(100 mg, 4.2 mmol) was added in portions at RT and stirred at RT for 10min. A solution of 2-(2-fluoro-4-methoxyphenyl)oxirane (353 mg, 2.10mmol) in DMF (2 mL) was added dropwise for 10 min. and stirred for 14 hat RT. The reaction was monitored by TLC and LCMS. The reaction mixturewas quenched with ice water, extracted in ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate and evaporated underreduced pressure. The crude product was purified by reverse phasechromatography to get pure product2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluoro-4-methoxyphenyl)ethanolas the TFA salt (300 mg).

Example 82 Preparation of2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(4-fluorophenyl)ethanol(Compound No. 51)

The title compound was prepared by following general procedure 5.9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg,1.27 mmol) was taken into DMF (8 mL). To a solution of sodium hydride(50%) (92 mg, 3.83 mmol) was added in portions at RT and stirred at RTfor 5 min. A solution of 2-(4-fluorophenyl)oxirane (264 mg, 1.92 mmol)in DMF (2 mL) was added dropwise for 10 min. and stirred for 14 h at RT.The reaction was monitored by TLC and LCMS. The reaction mixture wasquenched with ice water, extracted in ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and evaporated under reducedpressure. The crude product was purified by reverse phase chromatographyto get pure product2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-fluorophenyl)ethanolas the TFA salt (90 mg).

Example 83 Preparation of1-(4-fluorophenyl)-2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)ethanol(Compound No. 52)

The title compound was prepared by following general procedure 5.3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.40mmol) was taken into DMF (8 mL). To a solution of sodium hydride (50%)(100 mg, 4.2 mmol) was added in portions at RT and stirred at RT for 10min. A solution of 2-(4-fluorophenyl)oxirane (290 mg, 2.10 mmol) in DMF(2 mL) was added dropwise for 10 min. and stirred for 14 h at RT. Thereaction was monitored by TLC and LCMS. The reaction mixture wasquenched with ice water, extracted in ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and evaporated under reducedpressure. The crude product was purified by reverse phase chromatographyto get pure product2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-fluorophenyl)ethanolas the TFA salt (150 mg).

Example 84 Preparation ofCyclopentyl-2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)acetate(Compound No. 55)

The title compound was prepared by following general procedure 9.3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46mmol), was taken into DMF. CuI (9 mg, 0.046 mmol), L-proline (11 mg,0.093 mmol), K₃PO₄ (198 mg, 0.93 mmol) was added to the solution andstirred for 10 min. at RT cyclopentyl 2-chloroacetate (90 mg, 0.56 mmol)was added dropwise. The reaction mixture was heated at 90° C. for 12 h.After completion of reaction, the reaction mixture was filtered throughCelite. DMF was evaporated under reduced pressure and then extractedwith ethyl acetate. The organic layer was dried over Na₂SO₄, andconcentrated under reduced pressure. To obtain 20 mg of cyclopentyl2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetate.Then purified compound was taken into ethanol in HCl to gives HCl saltof desired compound.

Example 85 Preparation of2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(3,4-difluorophenyl)ethanol(Compound No. 58)

The title compound was prepared by following general procedure 5.9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (500 mg,2.13 mmol) was taken into DMF (8 mL). To a solution of sodium hydride(50%) (153 mg, 6.39 mmol) was added in portions at RT and stirred at RTfor 10 min. A solution of 2-(3,4-difluorophenyl)oxirane (498 mg, 3.19mmol) in DMF (4 mL) was added dropwise for 10 min. and stirred for 14 hat RT. The reaction was monitored by TLC and LCMS. The reaction mixturewas quenched with ice water, extracted in ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate and evaporated underreduced pressure. The crude product was purified by reverse phasechromatography to get pure product2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(3,4-difluorophenyl)ethanolas the TFA salt (180 mg).

Example 86 Preparation of1-(2,4-difluorophenyl)-2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)ethanol(Compound No. 59)

The title compound was prepared by following general procedure 5.3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (500 mg, 2.33mmol) was taken into DMF (6 mL). To a solution of sodium hydride (50%)(168 mg, 7.00 mmol) was added in portions at RT and stirred at RT for 10min. A solution of 2-(2,4-difluorophenyl)oxirane (546 mg, 3.50 mmol) inDMF (4 mL) was added dropwise for 10 min. and stirred for 14 h at RT.The reaction was monitored by LCMS. The reaction mixture was quenchedwith ice water, extracted in ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate and evaporated underreduced pressure. The crude product was purified by reverse phasechromatography to get pure product2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluorophenyl)ethanolas the TFA salt (60 mg).

Example 87 Preparation of2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(3-fluoro-4-methoxyphenyl)ethanol(Compound No. 67)

The title compound was prepared by following general procedure 5.9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg,1.27 mmol) was taken into DMF (6 mL). Sodium hydride (50%) (92 mg, 3.83mmol) was added in portions at RT and stirred at RT for 10 min. Asolution of 2-(3-fluoro-4-methoxyphenyl)oxirane (322 mg, 1.92 mmol) inDMF (4 mL) was added dropwise for 10 min. and stirred for 14 h at RT.The reaction was monitored by TLC and LCMS. The reaction mixture wasquenched with ice water, extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and evaporated under reducedpressure. The crude product was purified by reverse phase chromatographyto get pure product2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(3-fluoro-4-methoxyphenyl)ethanolas the TFA salt (200 mg).

Example 88 Preparation of1-(3-fluoro-4-methoxyphenyl)-2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)ethanol(Compound No. 68)

The title compound was prepared by following general procedure 5.3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.40mmol) was taken into DMF (6 mL). To a solution of sodium hydride (50%)(100 mg, 4.20 mmol) was added in portions at RT and stirred at RT for 10min. A solution of 2-(3-fluoro-4-methoxyphenyl)oxirane (353 mg, 2.10mmol) in DMF (4 mL) was added dropwise and stirred for 14 h at RT. Thereaction was monitored by TLC and LCM S. The reaction mixture wasquenched with ice water, extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous sodium sulfate andevaporated under reduced pressure. The crude product was purified byreverse phase chromatography to get pure product2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(3-fluoro-4-methoxyphenyl)ethanolas the TFA salt (250 mg).

Example 89 Preparation ofBenzyl-2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)acetate(Compound No. 75)

The title compound was prepared by following general procedure 9.Preparation of benzyl2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetate.9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg,0.43 mmol), was taken into DMF. To the above solution CuI (8 mg, 0.043mmol), L-proline (9 mg, 0.086 mmol), K₃PO₄ (183 mg, 0.86 mmol) was addedand stirred for 10 min. at RT. Benzyl 2-chloroacetate (95 mg, 0.51 mmol)was added dropwise. The reaction mixture was heated at 90° C. for 12 h.After completion of reaction, the reaction mixture was filtered throughCelite. DMF was evaporated under reduced pressure and then extractedwith ethyl acetate. The organic layer was dried over Na₂SO₄, andconcentrated under reduced pressure, to afford 90 mg of benzyl2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetateas the TFA salt after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).

Example 90 Preparation of2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(3,4-dimethoxyphenyl)ethanol(Compound No. 77)

The title compound was prepared by following general procedure 5.9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg,1.27 mmol) was taken into DMF (6 mL). Sodium hydride (50%) (92 mg, 3.83mmol) was added in portions at RT and stirred at RT for 10 min. Asolution of 2-(3,4-dimethoxyphenyl)oxirane (345 mg, 1.92 mmol) in DMF (4mL) was added dropwise for 10 min. and stirred for 14 h at RT. Thereaction was monitored by TLC and LCMS. The reaction mixture wasquenched with ice water, extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and evaporated under reducedpressure. The crude product was purified by reverse phase chromatographyto get pure product2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(3,4-dimethoxyphenyl)ethanolas the TFA salt (8 mg).

Example 91 Preparation of9-chloro-6-((E)-2-(4-fluorophenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole(Compound No. 2 and Compound No. 82)

The title compound was prepared by following general procedure 6.1-(9-Chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(4-fluorophenyl)propan-2-ol(100 mg, 0.259 mmol) was taken into 2.0 mL of 25% H₂SO₄ in water, andstirred at 90° C. for 3 h. The reaction was monitored by TLC and LCMS.The reaction mixture was cooled and basified with aq. KOH solution andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and evaporated under reduced pressure. The crude productwas purified using reverse phase chromatography to afford 12 mg ofproduct as the TFA salt along with9-chloro-6-(2-(4-fluorophenyl)allyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.Compound No. 82: ¹H NMR (CDCl₃, freebase) δ (ppm): 7.50-7.30 (m, 3H),7.20-7.00 (m, 4H), 7.30-7.20 (d, 1H), 5.00-4.90 (t, 2H), 4.40-4.30 (d,1H), 3.10-2.90 (m, 8H), 2.60 (s, 3H).

Example 92 Preparation of6-((E)-2-(4-chlorophenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole(Compound No. 33)

The title compound was prepared by following general procedure 6.2-(4-Chlorophenyl)-1-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)propan-2-ol(100 mg, 0.261 mmol) was taken into 2.0 mL of 25% H₂SO₄ in water, andstirred at 90° C. for 2 h. The reaction was monitored by LCMS. Thereaction mixture was cooled and basified with aq. KOH solution andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and evaporated under reduced pressure. The crude productwas purified using reverse phase chromatography to afford 10 mg ofproduct as the TFA salt along with6-(2-(4-chlorophenyl)allyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.

Example 93 Preparation of6-((E)-2-(4-fluorophenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole(Compound No. 34)

The title compound was prepared by following general procedure 6.1-(3,9-Dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(4-fluorophenyl)propan-2-ol(100 mg, 0.273 mmol) was taken into 2.0 mL of 25% H₂SO₄ in water, andstirred at 90° C. for 2 h. The reaction was monitored by TLC and LCMS.The reaction mixture was cooled and basified with aq. KOH solution andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and evaporated under reduced pressure. The crude productwas purified using reverse phase chromatography to afford 10 mg ofproduct as the TFA salt along with6-(2-(4-fluorophenyl)allyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.

Example 94 Preparation of9-chloro-6-((E)-2-(4-chlorophenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole(Compound No. 36 and Compound No. 35)

The title compound was prepared by following general procedure 6.1-(9-Chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(4-chlorophenyl)propan-2-ol (100 mg, 0.248 mmol) was taken into 2.0 mL of 25%H₂SO₄ in water and stirred at 90° C. for 2 h. The reaction was monitoredby LCMS. The reaction mixture was cooled and basified with aq. KOHsolution and extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate and evaporated under reduced pressure. Thecrude product was purified using reverse phase chromatography to obtainthe title compound as the TFA salt along with9-chloro-6-(2-(4-chlorophenyl)allyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.

Example 95 Preparation of6-(4-methoxystyryl)-9-chloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole(Compound No. 78)

The title compound was prepared by following general procedure 6. To asolution of2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-methoxyphenyl)ethanol(100 mg, 0.25 mmol) in DCM (2 mL), triethylamine (0.053 mL, 0.38 mmol)was added and stirred for 10 min., methane sulfonyl chloride (0.02 mL,0.27 mmol) was added slowly at 0° C. and stirred at the same temperaturefor 1 h and stirred at RT for 2 h. The reaction mixture was diluted withwater, extracted with DCM. The organic layer was dried over anhydroussodium sulfate and evaporated under reduced pressure. The crude productwas purified by column chromatography. Pure product was taken into NMP(2.0 mL), KOH powder (72 mg, 1.2 mmol) was added at RT and heated at 80°C. for 24 h. The product was detected by LCMS, the reaction mixture wasdiluted with water, extracted with ethyl acetate. The organic layer wasdried over anhydrous sodium sulfate, concentrated and crude product waspurified by reverse phase chromatography to get 6 mg of pure product asthe TFA salt.

Example 96 Preparation ofN-cyclohexyl-2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)acetamide(Compound No. 22)

The title compound was prepared by following general procedure 7.3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46mmol), was taken into DMF. CuI (9 mg, 0.045 mmol), L-proline (11 mg,0.093 mmol), K₃PO₄ (198 mg, 0.93 mmol) was added to the solution andstirred for 10 min. at RT. 2-chloro-N-cyclohexylacetamide (98 mg, 0.56mmol) was added dropwise. The reaction mixture was heated at 90° C. for12 h. After completion of reaction, the reaction mixture was filteredthrough Celite. DMF was evaporated under reduced pressure and thenextracted with ethyl acetate. The organic layer was dried over anhydrousNa₂SO₄, and concentrated under reduced pressure. And purified by columnchromatography and then oxalate salt was made by using oxalic acid (35mg, 0.46 mmol) to obtain 100 mg ofN-cyclohexyl-2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamideas the oxalate salt.

Example 97 Preparation of2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-N-isopropylacetamide(Compound No. 31)

The title compound was prepared by following general procedure 7.9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg,0.43 mmol), was taken into DMF. CuI (8 mg, 0.043 mmol), L-proline (9 mg,0.086 mmol), K₃PO₄ (183 mg, 0.86 mmol) was added to the solution andstirred for 10 min. at RT. 2-Chloro-N-isopropylacetamide (65 mg, 0.51mmol) was added dropwise. The reaction mixture was heated at 90° C. for12 h. After completion of reaction, the reaction mixture was filteredthrough Celite. DMF was evaporated under reduced pressure and then theresidue was extracted with ethyl acetate. The organic layer was driedover Na₂SO₄, and concentrated under reduced pressure to obtain 40 mg of2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-isopropylacetamideas the TFA salt after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).

Example 98 Preparation of2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-1-(piperidin-1-yl)ethanone(Compound No. 32)

The title compound was prepared by following general procedure 7.3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.47mmol), was taken into DMF. CuI (9 mg, 0.046 mmol), L-proline (11 mg,0.093 mmol), K₃PO₄ (198 mg, 0.93 mmol) were added to the solution andstirred for 10 min. at RT. 2-Chloro-1-(piperidin-1-yl)ethanone (91 mg,0.56 mmol) was added dropwise. The reaction mixture was heated at 90° C.for 12 h. After completion of reaction, the reaction mixture wasfiltered through Celite. DMF was evaporated under reduced pressure andthen extracted with ethyl acetate. The organic layer was dried overNa₂SO₄, and concentrated under reduced pressure to obtain 14 mg of2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(piperidin-1-yl)ethanoneas the TFA salt after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).

Example 99 Preparation of2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-N-(4-fluorophenyl)acetamide(Compound No. 37)

The title compound was prepared by following general procedure 7.9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg,0.43 mmol), was taken into DMF. CuI (8 mg, 0.043 mmol), L-proline (9 mg,0.086 mmol), K₃PO₄ (183 mg, 0.86 mmol) were added to the solution andstirred for 10 min. at RT. 2-Chloro-N-(4-fluorophenyl)acetamide (96 mg,0.53 mmol) was added dropwise. The reaction mixture was heated at 90° C.for 12 h. After completion of reaction, the reaction mixture wasfiltered through Celite. DMF was evaporated under reduced pressure andthen extracted with ethyl acetate. The organic layer was dried overNa₂SO₄, and concentrated under reduced pressure, to obtain 20 mg of2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-fluorophenyl)acetamide as the TFA salt after purification by reverse-phasechromatography (C-18, 5 00 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min.,injection vol. 5 mL).

Example 100 Preparation of2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-1-morpholinoethanone(Compound No. 38)

The title compound was prepared by following general procedure 7.3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46mmol), was taken into DMF. To the above solution CuI (9 mg, 0.046 mmol),L-proline (11 mg, 0.093 mmol), K₃PO₄ (198 mg, 0.93 mmol) were added andstirred for 10 min. at RT. 2-Chloro-1-morpholinoethanone (91 mg, 0.56mmol) was added dropwise. The reaction mixture was heated at 90° C. for12 h. After completion of reaction, the reaction mixture was filteredthrough Celite. DMF was evaporated under reduced pressure and thenextracted with ethyl acetate. The organic layer was dried over Na₂SO₄,and concentrated under reduced pressure. To obtain 4 mg of2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-morpholinoethanoneas the TFA salt after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).

Example 101 Preparation ofN-(4-fluorophenyl)-2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)acetamide(Compound No. 44)

The title compound was prepared by following general procedure 7.3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46mmol), was taken into DMF. To the above solution CuI (9 mg, 0.046 mmol),L-proline (11 mg, 0.093 mmol), K₃PO₄ (198 mg, 0.93 mmol) were added andstirred for 10 min. at RT. 2-Chloro-N-(4-fluorophenyl)acetamide (105 mg,0.56 mmol) was added dropwise. The reaction mixture was heated at 90° C.for 12 h. After completion of reaction, the reaction mixture wasfiltered through Celite. DMF was evaporated under reduced pressure andthen extracted with ethyl acetate. The organic layer was dried overNa₂SO₄, and concentrated under reduced pressure to obtain 104 mg of2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-fluorophenyl)acetamideas the TFA salt after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).

Example 102 Preparation of2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-1-(pyrrolidin-1-yl)ethanone(Compound No. 45)

The title compound was prepared by following general procedure 7.3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46mmol), was taken into DMF. To the above solution CuI (9 mg, 0.046 mmol),L-proline (11 mg, 0.093 mmol), K₃PO₄ (198 mg, 0.93 mmol) were added andstirred for 10 min. at RT. 2-Chloro-1-(pyrrolidin-1-yl)ethanone (82 mg,0.56 mmol) was added dropwise. The reaction mixture was heated at 90° C.for 12 h. After completion of reaction, the reaction mixture wasfiltered through Celite. DMF was evaporated under reduced pressure andthen extracted with ethyl acetate. The organic layer was dried overNa₂SO₄, and concentrated under reduced pressure to obtain 4 mg of2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyrrolidin-1-yl)ethanoneas the TFA salt after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).

Example 103 Preparation of2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(pyrrolidin-1-yl)ethanone(Compound No. 53)

The title compound was prepared by following general procedure 7.9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg,0.43 mmol), was taken into DMF. CuI (8 mg, 0.043 mmol), L-proline (10mg, 0.086 mmol), K₃PO₄ (183 mg, 0.86 mmol) were added to the solutionand stirred for 10 min. at RT. 2-chloro-1-(pyrrolidin-1-yl)ethanone (75mg, 0.51 mmol) was added dropwise. The reaction mixture was heated at90° C. for 12 h. After completion of reaction, the reaction mixture wasfiltered through Celite. DMF was evaporated under reduced pressure andthen extracted with ethyl acetate. The organic layer was dried overNa₂SO₄, and concentrated under reduced pressure to obtain 15 mg of2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyrrolidin-1-yl)ethanoneas the TFA salt after purification by reverse-phase chromatography(C-18, 5 00 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).

Example 104 Preparation of2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-N-isopropylacetamide(Compound No. 54)

The title compound was prepared by following general procedure 7.3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46mmol), was taken into DMF. CuI (9 mg, 0.046 mmol), L-proline (11 mg,0.093 mmol), K₃PO₄ (198 mg, 0.93 mmol) were added to the solution andstirred for 10 min. at RT. 2-Chloro-N-isopropylacetamide (76 mg, 0.56mmol) was added dropwise. The reaction mixture was heated at 90° C. for12 h. After completion of reaction, the reaction mixture was filteredthrough Celite. DMF was evaporated under reduced pressure and thenextracted with ethyl acetate. The organic layer was dried over Na₂SO₄,and concentrated under reduced pressure to obtain 7 mg of2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-isopropylacetamideas the TFA salt after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).

Example 105 Preparation of2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(piperidin-1-yl)ethanone(Compound No. 57)

The title compound was prepared by following general procedure 7.9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg,0.43 mmol), was taken into DMF. To the above solution CuI (8 mg, 0.043mmol), L-proline (9 mg, 0.086 mmol), K₃PO₄ (183 mg, 0.86 mmol) wereadded and stirred for 10 min. at RT. 2-Chloro-1-(piperidin-1-yl)ethanone(83 mg, 0.51 mmol) was added dropwise. The reaction mixture was heatedat 90° C. for 12 h. After completion of reaction, the reaction mixturewas filtered through Celite. DMF was evaporated under reduced pressureand then extracted with ethyl acetate. The organic layer was dried overNa₂SO₄, and concentrated under reduced pressure to obtain 6 mg of2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(piperidin-1-yl)ethanoneas the TFA salt after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).

Example 106 Preparation of2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-morpholinoethanone(Compound No. 60)

The title compound was prepared by following general procedure 7.9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg,0.43 mmol), was taken into DMF. To the above solution CuI (8 mg, 0.043mmol), L-proline (9 mg, 0.086 mmol), K₃PO₄ (183 mg, 0.86 mmol) wereadded and stirred for 10 min. at RT. 2-Chloro-1-morpholinoethanone (84mg, 0.51 mmol) was added dropwise. The reaction mixture was heated at90° C. for 12 h. After completion of reaction, the reaction mixture wasfiltered through Celite. DMF was evaporated under reduced pressure andthen extracted with ethyl acetate. The organic layer was dried overNa₂SO₄, and concentrated under reduced pressure to obtain 21 mg of2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-morpholinoethanoneas the TFA salt after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).

Example 107 Preparation of2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(piperazin-1-yl)ethanone(Compound No. 72)

The title compound was prepared by following general procedure 7.9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg,0.43 mmol), was taken into DMF. CuI (8 mg, 0.043 mmol), L-proline (10mg, 0.086 mmol), K₃PO₄ (183 mg, 0.85 mmol) were added to the solutionand stirred for 10 min. at RT. 2-Chloro-1-(piperazin-1-yl)ethanone(0.135 mg, 0.51 mmol) was added dropwise. The reaction mixture washeated at 90° C. for 12 h. After completion of reaction, the reactionmixture was filtered through Celite. DMF was evaporated under reducedpressure and then extracted with ethyl acetate. The organic layer wasdried over Na₂SO₄, and concentrated under reduced pressure. The crudecompound was purified by column chromatography to gives 35 mg, and thenthe compound was stirred in ethanolic HCl to give the HCl salt of2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(piperazin-1-yl)ethanone.

Example 108 Preparation of2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-N-phenylacetamide(Compound No. 73)

The title compound was prepared by following general procedure 7.9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg,0.43 mmol), was taken into DMF. CuI (8 mg, 0.043 mmol), L-proline (10mg, 0.086 mmol), K₃PO₄ (183 mg, 0.86 mmol) was added to the solution andstirred for 10 min. at RT. 2-Chloro-N-phenylacetamide (87 mg, 0.51 mmol)was added dropwise. The reaction mixture was heated at 90° C. for 12 h.After completion of reaction, the reaction mixture was filtered throughCelite. DMF was evaporated under reduced pressure and then extractedwith ethyl acetate. The organic layer was dried over Na₂SO₄, andconcentrated under reduced pressure to obtain 40 mg of2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-phenylacetamideas the TFA salt after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobil e Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).

Example 109 Preparation of2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-N-cyclohexyl-N-methylacetamide(Compound No. 74)

The title compound was prepared by following general procedure 7.9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg,0.43 mmol), was taken into DMF. CuI (8 mg, 0.043 mmol), L-proline (10mg, 0.086 mmol), K₃PO₄ (183 mg, 0.86 mmol) were added to the solutionand stirred for 10 min. at RT. 2-Chloro-N-cyclohexyl-N-methylacetamide(98 mg, 0.51 mmol) was added dropwise. The reaction mixture was heatedat 90° C. for 12 h. After completion of reaction, the reaction mixturewas filtered through Celite. DMF was evaporated under reduced pressureand then extracted with ethyl acetate. The organic layer was dried overNa₂SO₄, and concentrated under reduced pressure to obtain 56 mg of2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-cyclohexyl-N-methylacetamideas the TFA salt after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).

Example 110 Preparation of2-(9-chloro-2,3,4,5-tetrahydro-3-methylazepino[4,5-b]indol-6(1H)-yl)-1-(4-methylpiperidin-1-yl)ethanone(Compound No. 76)

The title compound was prepared by following general procedure 7. Sodiumhydride (34 mg, 0.43 mmol) washed with hexane for removal of oil anddried under vacuum and taken in THF.

To this solution9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.1 g, 0.43mmol) in THF was added dropwise at 0° C. Then the reaction mixture wasstirred for 0.5 h. The solution of2-chloro-1-(4-methylpiperidin-1-yl)ethanone (89 mg, 0.51 mmol) in THFwas added dropwise in reaction mixture. Then the reaction mixture wasstirred at RT for 2 h. The reaction monitored by TLC. After completionof the reaction, the reaction mixture was quenched with ice water. THFwas evaporated and aqueous layer was extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate. The crudecompound was washed with hexane and diethyl ether for removal of colorimpurities then recrystallized by using methanol to gives 95 mg ofdesired compound, which was stirred with ethanolic HCl to give the HClsalt of2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-methylpiperidin-1-yl)ethanone.

Example 111 Preparation of2-(2,3,4,5-tetrahydro-3,9-dimethylazepino[4,5-b]indol-6(1H)-yl)-N-phenylacetamide(Compound No. 79)

The title compound was prepared by following general procedure 7.3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46mmol), was taken into DMF. CuI (9 mg, 0.046 mmol), L-proline (11 mg,0.093 mmol), K₃PO₄ (198 mg, 0.93 mmol) was added to the solution andstirred for 10 min. at RT. 2-Chloro-N-phenylacetamide (95 mg, 0.56 mmol)was added dropwise. The reaction mixture was heated at 90° C. for 12 h.After completion of reaction, the reaction mixture was filtered throughCelite. DMF was evaporated under reduced pressure and then extractedwith ethyl acetate. The organic layer was dried over Na₂SO₄, andconcentrated under reduced pressure. The crude compound was purified bycolumn chromatography to obtain2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-phenylacetamideas the HCl salt using ethanolic HCl (29 mg).

The compounds prepared according to the Examples are further detailed inTable 3.

TABLE 3 Synthetic Data FW Compound Salt MW (Salt NMR No. Type Free BaseIncluded) Solvent NMR_DATA 1 DiHCL 407.87 480.78 DMSO 11.0 (bs, 1H), 8.5(s, 1H), 7.8 (d, 1H), 7.7 (d, 1H), 7.5 (s, 1H), 7.4 (d, 1H), 7.0 (d,1H), 4.5 (t, 2H), 3.6 (bs, 2H), 3.3-3.0 (m, 8H), 2.9 (s, 3H), 4 TFA353.90 467.91 CD3OD 10.13 (bs, 1H), 9.10 (bs, 1H), 8.42 (s, 1H), 8.22(s, 1H), 7.70 (s, 1H), 7.26 (d, 1H), 7.10 (s, 1H), 6.90 (d, 1H),4.17-4.22 (m, 2H), 3.10-3.21 (m, 5H), 2.83-3.07 (m, 8H), 2.40 (t, 3H) 5TFA 339.87 453.89 CD3OD 10.0 (bs, 1H), 8.55 (d, 2H2H), 7.57 (d, 1H),7.40-7.45 (m, 3H), 7.07 (dd, 1H), 4.50 (t, 2H), 3.50-3.63 (m, 4H),3.15-3.23 (m, 6H), 2.90 (t, 3H). 6 TFA 319.45 433.47 CD3OD 10.1 (bs,1H), 8.60 (d, 2H), 7.50 (d, 2H), 7.11-7.20 (m, 2H), 6.90 (d, 1H), 4.42(t, 2H), 3.10-3.25 (m, 6H), 3.05 (t, 4H), 2.95 (s, 3H), 2.45 (s, 3H). 8TFA 339.87 453.89 DMSO 8.60-8.56 (d, 1H), 8.20-8.10 (t, 1H), 7.70-7.60(t, 1H), 7.60-7.50 (d, 1H), 7.40 (s, 1H), 7.20-7.10 (d, 1H), 7.00-6.90(d, 1H), 4.50-4.40 (t, 2H), 3.60-3.30 (t, 4H), 3.30-3.10 (m, 6H), 2.90(s, 3H). 9 TFA 319.45 433.47 DMSO 8.60-8.50 (d, 1H), 8.10-8.00 (t, 1H),7.60-7.50 (t, 1H), 7.50-7.40 (d, 1H), 7.20 (s, 1H), 7.18-7.11 (d, 1H),6.90-6.80 (d, 1H), 4.50-4.40 (t, 2H), 3.60-3.50 (t, 2H), 3.30-3.10 (m,8H), 2.90 (s, 3H), 2.30 (s, 3H). 10 TFA 374.32 488.33 DMSO 8.54-8.45 (m,1H), 8.30-8.25 (s, 1H), 7.75-7.70 (d, 1H), 7.60-7.55 (d, 1H), 7.50-7.45(d, 1H), 7.05 (d, 1H), 4.5-4.40 (m, 2H), 3.70-3.55 (m, 2H), 3.30-3.10(m, 6H), 3.05-2.85 (m, 5H). 11 TFA 363.46 477.48 DMSO 2.35-2.40 (s, 3H),2.65-2.80 (m, 2H), 2.85-2.95 (m, 5H), 3.02-3.20 (m, 6H), 4.35-4.50 (t,2H), 6.90-6.95 (d, 1H), 7.25-7.35 (m, 2H), 7.65-7.70 (d, 1H), 7.90-7.95(d, 1H), 8.32-8.35 (s, 1H), 9.75-9.90 (m, 1H). 12 TFA 403.36 517.37 DMSO7.50-7.20 (m, 6H), 7.00-6.90 (t, 1H), 4.30-4.20 (d, 2H), 4.20-4.10 (d,2H), 3.60-3.40 (m, 2H), 3.30-3.00 (m, 4H), 2.90 (s, 3H), 1.50-1.40 (d,3H). 14 OXALATE 366.48 456.51 DMSO 7.50-7.40 (t, 2H), 7.30-7.00 (m, 4H),6.90-6.80 (d, 1H), 4.30-20 (d, 2H), 4.20-4.10 (d, 2H), 3.20-3.00 (m,6H), 2.90 (s, 3H), 2.30 (s, 3H), 1.40 (t, 3H). 15 OXALATE 382.94 472.96DMSO 7.50-7.40 (d, 2H), 7.40-7.20 (m, 3H), 6.90-6.70 (dd, 2H), 4.30-4.20(d, 2H), 4.20-4.00 (d, 2H), 3.20-3.00 (m, 6H), 2.90 (s, 3H), 2.30 (s,3H), 1.40 (s, 3H). 16 TFA 389.33 503.34 DMSO 7.50-7.40 (t, 1H),7.38-7.18 (m, 5H), 7.10-7.00 (d, 1H), 4.80-4.70 (d, 2H), 4.30-4.20 (d,2H), 3.60-3.50 (m, 4H), 3.20-3.00 (m, 2H), 2.90 (s, 3H).. 17 TFA 368.91482.92 DMSO 7.40-7.20 (m, 6H), 6.98-6.80 (d, 1H), 4.90-4.70 (dd, 2H),4.30-4.10 (t, 2H), 3.60-3.40 (m, 2H), 3.30-3.00 (m, 4H), 2.90 (s, 3H),2.30 (s, 3H). 18 TFA 355.87 469.88 DMSO 8.70-8.50 (dd, 2H), 8.30-8.20(d, 1H), 7.80-7.70 (m, 1H), 7.50-7.40 (t, 1H), 7.30-7.20 (m, 1H),7.10-6.90 (t, 1H), 5.10-5.00 (m, 2H), 4.20-4.10 (t, 2H), 3.70-3.58 (m,2H), 3.40-3.20 (m, 4H), 2.90 (s, 3H). 19 TFA 335.45 449.47 DMSO8.80-8.60 (dd, 2H), 8.30-8.20 (d, 1H), 7.90-7.70 (m, 1H), 7.10-7.00 (t,1H), 7.00-6.90 (m, 1H), 6.90-6.80 (t, 1H), 5.10-5.00 (m, 2H), 4.40-4.30(d, 2H), 3.70-3.50 (m, 2H), 3.40-3.00 (m, 4H), 2.90 (s, 3H), 2.25 (s,3H). 20 TFA 387.45 501.46 DMSO 10.1-9.9 (m, 1H), 8.45 (s, 1H), 7.95-7.75(m, 2H), 7.30-7.20 (m, 2H), 6.95-6.85 (d, 1H), 4.50-4.35 (t, 2H),3.23-3.00 (m, 8H), 2.95-2.85 (m, 6H), 2.35 (s, 3H). 21 TFA 383.88 497.89DMSO 10.05-9.95 (m, 1H), 8.35 (s, 1H), 7.9-7.85 (d, 1H), 7.75-7.65 (d,1H), 7.60-7.55 (s, 1H), 7.50-7.40 (d, 1H), 7.10-7.05 (d, 1H), 4.55-4.40(m, 2H), 3.25-2.80 (m, 13H). 22 OXALATE 353.51 443.54 DMSO −10.9 (s,1H), 8.62 (d, 1H), 7.19-7.22 (m, 2H), 6.90 (d, 1H), 4.25 (s, 2H),3.6-4.0 (m, 6H), 3.2-3.4 (m, 6H), 2.4 (s, 3H), 1.5-1.9 (m, 5H), 1.1-1.4(m, 5H). 23 TFA 349.48 463.49 DMSO 10.8 (s, 1H) 8.97 (s, 1H) 7.90-7.84(m, 1H) 7.43-7.37 (m, 1H), 7.25-7.15 (m, 1H), 6.70-6.10 (m, 2H),5.42-5.38 (d, 1H), 4.10-3.70 (m, 6H) 3.20-3.0 (m, 4H) 2.70 (S, 3H) 2.50(s, 3H) 2.38 (s, 3H). 24 TFA 354.88 468.90 DMSO 7.80-7.70 (t, 1H),7.70-7.60 (t, 1H), 7.38-7.30 (m, 5H), 7.20-7.0 (d, 1H), 4.85-4.80 (m,2H), 4.30-4.20 (d, 4H), 3.0-2.80 (m, 7H). 25 TFA 334.47 448.48 DMSO7.40-7.25 (m, 6H), 6.95-6.85 (d, 2H), 4.80-4.75 (t, 2H), 4.35-4.25 (m,4H), 3.0-2.80 (m, 7H), 2.35 (s, 3H). 26 TFA 368.91 482.92 DMSO 7.50-7.40(m, 2H), 7.20-7.0 (m, 5H), 4.80-4.70 (d, 2H), 4.25-4.20 (t, 4H),3.25-3.10 (m, 4H), 3.0-2.95 (s, 3H), 2.25 (s, 3H). 27 TFA 348.49 462.50DMSO 7.40-7.20 (m, 5H), 7.0-6.90 (d, 2H), 4.82-4.70 (d, 2H), 4.30-4.10(m, 4H), 3.15-2.95 (m, 4H), 2.95-2.90 (t, 3H), 2.40 (s, 3H), 2.30 (s,3H). 28 TFA 352.91 466.92 CD3OD 1H NMR 7.40-7.10 (m, 3H), 7.10-7.00 (d,2H), 6.90-6.80 (d, 2H), 4.40-4.30 (t, 2H), 3.20-3.10 (m, 8H), 3.10-3.00(t, 2H), 3.00 (s, 3H), 2.40 (s, 3H) 29 TFA 373.33 487.34 CD3OD 7.60 (s,1H), 7.45-7.38 (m, 2H), 7.32-7.05 (m, 4H), 4.42-4.37 (t, 2H), 3.70-3.37(m, 4H), 3.30-3.0 (m, 6H), 2.90 (s, 3H) 30 TFA 373.33 487.34 CD3OD 7.58(s, 1H), 7.50-7.45 (d, 1H), 7.35-7.25 (m, 2H), 7.16-7.06 (m, 3H),4.41-4.36 (t, 2H), 3.72-3.50 (m, 4H), 3.30-3.0 (m, 6H) 2.90 (s, 3H). 31TFA 333.86 447.88 DMSO −11.23 (s, 1H), 8.53 (d, 1H), 7.52 (s, 1H,), 7.30(d, 1H), 7.24 (d, 1H), 4.80 (d, 1H), 4.70 (d, 1H), 4.11-4.27 (m, 2H),3.75-4.0 (m, 5H), 3.10-3.39 (m, 5H), 1.10 (d, 6H). 32 TFA 339.48 453.50CD3OD 7.23 (s, 1H), 7.19 (d, 1H), 6.94 (d, 1H), 4.60 (s, 2H), 4.18-4.29(m, 2H), 3.85-3.99 (m, 2H), 3.43-3.60 (m, 7H), 3.23-3.40 (m, 4H), 2.40(s, 3H), 1.50-1.76 (m, 6H). 10.7 (bs, 1H), 7.20-7.24 (m, 2H), 6.90 (d,1H), 5.20 (s, 2H), 3.46-3.63 (m, 4H), 3.30-3.40 (m, 2H), 3.09-3.13 (m,4H), 2.92-3.02 (m, 2H), 2.87 (s, 3H), 2.31 (s, 3H), 1.50-1.62 (m, 4 H),1.34-1.43 (m, 2H).. 33 TFA 364.92 478.93 DMSO 7.70-7.60 (d, 2H),7.50-7.40 (d, 2H), 7.30 (s, 2H), 7.10-6.90 (m, 2H), 3.70-3.40 (m, 4H),2.95 (s, 3H), 2.35 (s, 3H), 1.80-1.70 (m, 4H). 34 TFA 348.47 462.48 DMSO7.70-7.60 (t, 2H0, 7.35-7.20 (m, 2H), 7.02-6.90 (m, 3H), 3.70-3.50 (m,4H), 3.30-3.20 (m, 5H), 2.95 (s, 3H), 2.35 (s, 3H), 1.90-1.80 (t, 2H).35 TFA 385.34 499.35 DMSO 7.60-7.50 (d, 4H), 7.40-7.30 (m, 2H),7.15-7.00 (m, 1H), 5.30 (s, 1H), 5.10 (s, 1H), 3.70-3.50 (m, 4H),3.35-3.20 (m, 4H), 2.95 (s, 3H). 36 TFA 385.34 499.35 DMSO 7.75-7.60 (m,2H), 7.60 (s, 1H), 7.50-7.40 (d, 2H), 7.25-7.20 (m, 2H), 7.00 (s, 1H),5.30-5.20 (m, 2H), 3.70-3.50 (m, 3H), 3.45-3.35 (m, 2H), 3.10 (s, 3H),1.95-1.90 (t, 4H). 2 TFA 368.89 482.90 DMSO 7.75-7.60 (m, 2H), 7.65 (s,1H), 7.35-7.20 (t, 4H), 6.95 (s, 1H), 3.75-3.40 (m, 4H), 3.30-3.20 (m,5H), 2.95 (s, 2H), 1.95-1.90 (t, 2H). 37 TFA 385.87 499.89 DMSO 11.3 (s,1H), 10.9 (s, 1H), 7.60-7.63 (m, 2H), 7.56 (s, 1H), 7.35 (d, 1H), 7.24(t, 2H), 7.06 (d, 1H), 4.53 (s, 2H), 4.0-4.1 (m, 2H), 3.85-3.98 (m, 2H),3.43 (s, 3H), 3.3-3.39 (m, 2H), 3.19-3.24 (m, 2H). 38 TFA 341.46 455.47CD3OD 7.22 (s, 1H), 7.19 (d, 1H), 6.9 (d, 1H), 4.6 (s, 2H), 4.2-4.3 (m,3H), 3.85-4.0 (m, 3H), 3.45-3.7 (m, 7H), 3.4-3.42 (m, 4H), 3.10-3.25 (m,2H), 2.4 (s, 3H). 43 TFA 335.45 449.47 DMSO DMSO 8.70-8.50 (d, 2H),8.0-7.90 (m, 1H), 7.70-7.69 (d, 1H), 7.30-7.10 (m, 2H), 6.90-6.70 (m,1H), 5.10-5.00 (t, 1H), 4.40-4.20 (t, 2H), 3.70-3.60 (m, 4H), 3.30-3.10(m, 4H), 2.90 (s, 3H), 2.30 (s, 3H). 44 TFA 365.45 479.47 DMSO−10.7-10.9 (m, 2H), 7.52-7.62 (m, 2H), 7.10-7.25 (m, 3H), 6.9 (d, 2H),4.3-4.41 (m, 3H), 3.75-3.9 (m, 2H), 3.41 (s, 3H), 3.20-3.27 (m, 2H),3.10-3.19 (m, 2H), 3.0 (s, 1H), 2.30 (s, 3H). 45 TFA 325.46 439.47 CD3OD7.22 (s, 1H), 7.10 (d, 1H), 7.92 (d, 1H), 4.42-4.6 (m, 5H), 4.2-4.4 (m,4H), 3.9-4.1 (m, 3H), 3.4-3.6 (m, 4H), 2.28-2.42 (m, 4H), 1.8-2.1 (m,4H). 46 TFA 352.91 466.92 CD3OD 7.50 (s, 1H), 7.40-7.30 (d, 1H),7.20-7.10 (d, 1H), 7.00-6.90 (d, 2H), 6.90-6.80 (d, 2H), 4.40-4.30 (t,2H), 3.00-2.90 (t, 2H), 2.90 (s, 3H), 2.80-2.60 (m, 8H), 2.30 (s, 3H) 47TFA 384.91 498.92 DMSO 7.60-7.50 (t, 1H), 7.50-7.40 (d, 1H), 7.30-7.20(m, 2H), 7.10-7.00 (d, 1H), 6.90-6.80 (d, 2H), 4.80-4.70 (t, 1H),4.30-4.20 (t, 2H), 3.80 (s, 3H), 3.70-3.50 (m, 4H), 3.30-3.10 (m, 4H),2.90 (s, 3H). 48 TFA 364.49 478.50 DMSO 7.40-7.10 (m, 4H), 7.00-6.80 (m,3H), 4.80-4.70 (t, 1H), 4.30-4.10 (m, 2H), 3.80 (s, 3H), 3.60-3.40 (m,4H), 3.20-3.00 (m, 4H), 2.90 (s, 3H), 2.30 (s, 3H). 49 TFA 402.90 516.91DMSO 7.60-7.50 (t, 1H), 7.50-7.30 (m, 2H), 7.10-7.05 (t, 1H), 6.90-6.70(m, 2H), 5.10-4.90 (t, 1H), 4.30-4.20 (t, 2H), 3.80 (s, 3H), 3.70-3.60(m, 4H), 3.30-3.10 (m, 4H), 2.90 (s, 3H). 50 TFA 382.48 496.49 DMSO7.50-7.40 (m, 1H), 7.30-7.20 (m, 2H), 7.00-6.90 (d, 1H), 6.90-6.70 (m,2H), 5.10-4.90 (t, 1H), 4.30-4.10 (t, 2H), 3.80 (s, 3H), 3.70-3.60 (m,4H), 3.30-3.10 (m, 4H), 2.90 (s, 3H), 2.30 (s, 3H). 51 TFA 372.87 486.89DMSO 7.60-7.50 (t, 1H), 7.50-7.30 (m, 3H), 7.20-7.00 (m, 3H), 4.90-4.70(t, 1H), 4.30-4.20 (t, 2H), 3.70-3.50 (m, 4H), 3.30-3.10 (m, 4H), 2.80(s, 3H). 52 TFA 352.46 466.47 DMSO 7.40-7.20 (m, 4H), 7.20-7.10 (m, 2H),6.90-6.85 (m, 1H), 4.90-4.70 (t, 1H), 4.30-4.10 (m, 2H), 3.30-3.10 (m,4H), 3.10-3.00 (m, 4H), 2.90 (s, 3H), 2.30 (s, 3H). 53 TFA 345.88 459.89CD3OD 7.41 (s, 1H), 7.21 (d, 1H), 7.02 (d, 1H), 4.5 (s, 2H), 4.2-4.35(m, 3H), 3.9-4.01 (m, 3H), 3.4-3.47 (m, 3H), 3.2-3.35 (m, 6H), 2.0-2.1(m, 2H), 1.9-1.99 (m, 2H). 54 TFA 313.45 427.46 CD3OD 8.4 (bs, 1H), 7.21(s, 1H), 7.19 (d, 1H), 6.9 (d, 1H), 4.22 (d, 1H), 3.96-4.18 (m, 3H),3.82-3.92 (m, 2H), 3.5 (s, 3H), 3.22-3.4 (m, 5H), 2.4 (s, 3H), 1.1 (d,6H). 55 HCL 340.47 376.92 CD3OD 7.21 (s, 1H), 7.19 (d, 1H), 6.9 (d, 1H),5.27-5.42 (m, 1H), 4.5 (s, 2H), 4.09-4.2 (m, 3H), 3.9-4.0 (m, 2H), 3.5(s, 3H), 2.4 (s, 3H), 1.9-2.1 (m, 2H), 1.7-1.85 (m, 6H). 56 OXALATE338.88 428.91 CD3OD 7.50 (s, 1H), 7.40-7.30 (d, 1H), 7.35-7.20 (m, 3H),7.20-7.10 (d, 1H), 7.00-7.80 (m, 2H), 4.40-4.30 (t, 2H), 3.40-3.30 (t,2H), 3.30-3.20 (t, 2H), 3.20-3.00 (t, 2H), 2.80 (s, 3H), 2.80-2.70 (m,4H). 57 TFA 359.90 473.92 CD3OD 7.42 (s, 1H), 7.22 (d, 1H), 7.09 (d,1H), 4.6 (s, 2H), 4.2-4.3 (m, 3H), 3.9-4.0 (m, 3H), 3.6-3.8 (m, 6H), 3.5(s, 3H), 3.4 (m, 3H), 1.45-1.9 (m, 6H). 10.7 (bs, 1H), 7.57 (s, 1H),7.40 (d, 1H), 7.06 (d, 1H), 5.20 (d, 2H), 3.55-3.63 (m, 4H), 3.47-3.54(m, 4H), 3.30-3.39 (m, 2H), 3.12-3.22 (m, 2H), 2.93-3.02 (m, 2H), 2.88(s, 3H), 1.50-1.67 (m, 4H), 1.35-1.48 (m, 2H). 58 TFA 390.86 504.88 DMSO7.62-7.50 (t, 1H), 7.50-7.30 (t, 3H), 7.25-7.00 (m, 2H), 4.85-4.75 (m,1H), 4.30-4.20 (t, 2H), 3.80-3.60 (m, 4H), 3.25-3.10 (m, 4H), 2.90 (s,3H). 59 TFA 370.45 484.46 DMSO 7.50-7.30 (m, 5H), 7.00-6.90 (t, 1H),4.85-4.70 (t, 1H), 4.30-4.15 (m, 2H), 3.35-3.15 (m, 4H), 3.00-2.90 (m,4H), 2.35 (s, 3H). 60 TFA 361.88 475.89 DMSO 11.2 (s, 1H), 7.5 (s, 1H),7.3 (d, 1H), 7.05 (d, 1H), 4.2-4.4 (m, 3H), 3.7-3.9 (m, 4H), 3.5-3.65(m, 4H), 3.42-3.49 (m, 6H), 3.3-3.4 (m, 6H), 3.12-3.2 (m, 3H). 61OXALATE 356.87 446.90 CD3OD 7.60-7.50 (m, 3H), 7.30-7.20 (m, 3H),7.20-7.10 (d, 1H), 4.00-3.80 (m, 6H), 3.80-3.70 (m, 4H), 3.60-3.50 (m,5H) 62 OXALATE 318.47 408.49 CD3OD 7.40-7.30 (m, 5H), 7.20 (m, 1H),7.20-7.10 (d, 1H), 7.0-6.80 (d, 1H), 4.0-3.80 (m, 4H), 3.80-3.70 (m,2H), 3.40 (s, 3H), 3.30-3.20 (m, 6H), 2.40 (s, 3H). 63 TFA 336.46 450.47CD3OD 7.40-7.20 (m, 3H), 7.20-7.00 (m, 3H), 6.90-6.80 (m, 1H), 4.40-4.20(m, 6H), 3.20-3.00 (m, 6H), 3.00 (s, 3H), 2.40 (s, 3H). 67 TFA 402.90516.92 DMSO 7.50 (s, 1H), 7.40-7.30 (t, 1H), 7.10-6.90 (m, 4H),4.80-4.70 (t, 1H), 4.30-4.20 (t, 2H), 3.80 (s, 3H), 3.60-3.50 (m, 2H),3.30-3.00 (m, 6H), 2.90 (s, 3H) 68 TFA 382.48 496.50 DMSO 7.30-7.20 (t,1H), 7.20-6.80 (m, 5H), 4.80-4.70 (t, 1H), 4.30-4.10 (m, 2H), 3.70 (s,3H), 3.20-3.00 (m, 8H), 2.90 (s, 3H), 2.30 (s, 3H). 69 TFA 352.91 466.93CD3OD 7.60-7.50 (m, 2H), 7.40-7.30 (m, 2H), 7.30 (s, 1H), 7.20-7.10 (d,1H), 7.0-6.90 (d, 1H), 4.0-3.80 (m, 4H), 3.70-3.50 (m, 2H), 3.40-3.20(m, 9H), 2.40 (s, 3H). 72 DiHCL 360.89 433.80 DMSO −11.3 (s, 1H), 9.5(bs, 1H), 7.5 (s, 1H), 7.3 (d, 1H), 7.02 (d, 1H), 4.77 (s, 2H), 4.0-4.2(m, 2H), 3.80-3.95 (m, 2H), 3.65-3.78 (m, 5H), 3.40 (s, 3H), 3.30-3.38(m, 2H), 3.20-3.26 (m, 4H), 3.12-3.18 (m, 2H). 73 TFA 367.88 481.90 DMSO−11.22 (s, 1H), 10.58 (s, 1H), 7.60 (d, 2H), 7.53 (s, 1H), 7.27-7.43 (m,3H), 7.04-7.20 (m, 2H), 4.48-4.50 (m, 2H), 3.82-4.10 (m, 6H), 3.50 (s,3H), 3.15-3.30 (m, 2H). 74 TFA 387.96 501.97 CD3OD 7.43 (s, 1H), 7.24(d, 1H), 7.04 (d, 1H), 4.55 (s, 2H), 4.18-4.40 (m, 3H), 3.90-4.20 (m,2H), 3.50 (s, 3H), 3.32-3.40 (m, 2H), 3.22-3.29 (m, 2H), 2.90 (s, 3H),1.10-1.90 (m, 10H). 75 TFA 382.89 496.91 DMSO −11.2 (s, 1H), 7.23-7.52(m, 6H), 7.05 (d, 2H), 5.30 (s, 2H), 5.16-5.20 (m, 2H), 4.70-4.83 (m,4H), 3.40 (s, 3H), 3.28-3.36 (m, 2H), 3.18-3.22 (m, 2H). 76 HCL 373.93410.38 DMSO −11.02 (bs, 1H), 7.57 (s, 1H), 7.38 (d, 1H), 7.04 (d, 1H),5.05-5.27 (m, 2H), 4.20-4.27 (m, 1H), 3.93-4.04 (m, 1H), 3.52-3.63 (m,2H), 3.0-3.26 (m, 4H), 2.90 (s, 3H), 2.50-2.63 (m, 4 H), 1.58-1.78 (m,3H), 1.03-1.30 (m, 2H), 0.94 (d, 3H). 77 TFA 414.94 528.94 DMSO 7.60 (s,1H), 7.50-7.40 (t, 1H), 7.10-7.00 (m, 2H), 6.95-6.85 (d, 2H), 5.60-5.50(m, 2H), 4.80-4.70 (m, 2H), 4.30-4.10 (m, 4H), 3.70 (s, 3H), 3.60 (s,3H), 3.30-3.10 (m, 2H), 2.95 (s, 3 H). 78 TFA 366.89 480.89 CD3OD7.60-7.50 (m, 2H), 7.50-7.40 (m, 2H), 7.20-7.18 (d, 1H), 7.10-6.90 (d,2H), 6.80-6.70 (d, 2H), 4.80-4.79 (d, 2H), 3.80 (s, 3H), 3.80-3.70 (m,3H), 3.40-3.30 (m, 2H), 3.10 (s, 3H). 79 HCL 347.46 383.92405 CD3OD 10.3(bs, 1H), 7.62 (d, 2H), 7.35 (t, 2H), 7.21 (s, 1H), 7.16-7.20 (m, 2H),6.93 (d, 1H), 4.40-4.50 (m, 2H), 4.20-4.30 (m, 3H), 3.90-4.05 (m, 2H),3.60 (s, 3H), 2.40 (s, 3H). 81 HCL 381.57 418.03 DMSO 10.62 (bs, 1H),7.23-7.30 (m, 2H), 6.90 (t, 1H), 4.17-4.40 (m, 2H), 3.03-3.34 (m, 7H),2.86-3.02 (m, 4H), 2.53-2.97 (m, 6H), 2.32 (s, 3H), 1.00-1.78 (m, 10H).

Example 126 Preparation ofN-cyclohexyl-2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-methylacetamide(Compound No. 232)

Sodium hydride (50%) (46 mg, 1.16 mmol) was dissolved in THF (2 mL) at0° C. and stirred for 10 min.3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46mmol) in THF (3 mL) was added dropwise to the reaction mixture at 0° C.and stirred for 10 min. A solution of2-chloro-N-cyclohexyl-N-methylacetamide (106 mg, 0.56 mmol) was added tothe reaction mixture which was stirred at RT for 2 h. The reactionmixture was quenched with ice water, and a white solid was obtained. Thesolid was filtered, washed with diethyl ether and dried under vacuum toobtain 80 mg of product. The product was treated with ethanolic HCl toafford 74 mg of product as the HCl salt. ¹H NMR (DMSO-d6, HCl salt) δ(ppm): 7.20 (m, 2H), 6.84 (d, 1H), 5.20-5.04 (m, 2H), 4.10 (m, 1H),3.80-3.70 (m, 4H), 3.20-3.00 (m, 8H), 2.90 (s, 2H), 2.42 (s, 3H),1.95-1.80 (m, 2H), 1.70-1.50 (m, 4H), 1.40-1.25 (m, 2H), 1.26-1.20 (m,2H).

Example 127 Preparation of(E)-6-(2-fluorostyryl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 233)

A solution of2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluorophenyl)ethanol(100 mg, 0.28 mmol), triethylamine (0.59 mL, 0.42 mmol) in DCM (6 mL),was stirred for 10 min. at 0° C. Methane sulfonyl chloride (0.026 mL,0.32 mmol) was added slowly at 0° C. and stirred at RT for 2 h. Thereaction mixture was diluted with water and extracted with DCM. Theorganic layer was dried over anhydrous sodium sulfate and evaporatedunder reduced pressure to obtain the crude product. The crude productwas dissolved in NMP (0.7 mL), KOH powder (160 mg, 2.8 mmol) was addedand heated at 90° C. for 14 h. The reaction was monitored by LCMS.Inorganic material was filtered off and the filtrate was purified byreverse phase chromatography to afford 20 mg of TFA salt. ¹H NMR (CD₃OD,TFA salt) δ (ppm): 7.70-7.60 (m, 2H), 7.50-7.40 (d, 1H), 7.40-7.20 (m,2H), 7.20-7.00 (m, 3H), 6.90-6.80 (d, 1H), 3.80-3.70 (m, 4H), 3.50-3.40(m, 4H), 3.15 (s, 3H), 2.40 (s, 3H).

Example 128 Preparation of(E)-9-chloro-6-(4-fluorostyryl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 234)

A solution of2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-fluorophenyl)ethanol(100 mg, 0.268 mmol) and triethylamine (0.055 mL, 0.402 mmol) in DCM (6mL) was stirred at 0° C. for 10 min. Methane sulfonyl chloride (0.022mL, 0.295 mmol) was added slowly at 0° C. and the reaction mixture wasstirred at RT for 2 h. The reaction mixture was diluted with water, andextracted with DCM. The organic layer was dried over anhydrous sodiumsulfate and evaporated under reduced pressure to obtain the crudeproduct. The crude product was dissolved in NMP (1 mL), KOH powder (105mg, 1.87 mmol) was added at RT and heated at 90° C. for 14 h. thereaction mixture was monitored by LCMS. Inorganic material was filteredoff and filtrate was purified by reverse phase chromatography to afford15 mg of TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.70-7.50 (m, 4H),7.20-7.10 (m, 3H), 6.80-6.70 (d, 2H), 3.80-3.70 (m, 2H), 3.50-3.40 (m,2H), 3.30-3.10 (d, 4H), 3.15 (s, 3H).

Example 129 Preparation of(E)-6-(4-chlorostyryl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 235)

1-(4-Chlorophenyl)-2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethanol(100 mg, 0.271 mmol) was dissolved in DCM (5 mL) and triethylamine(0.056 mL, 0.406 mmol) was added. The reaction mixture was stirred at 0°C. for 10 min. Methane sulfonyl chloride (0.023 mL, 0.298 mmol) wasadded slowly at 0° C. and the reaction mixture was stirred at RT for 2h. The reaction mixture was diluted with water and extracted with DCM.The organic layer was dried over anhydrous sodium sulfate and evaporatedunder reduced pressure to obtain the crude product. The crude productwas dissolved in NMP (0.8 mL), KOH powder (106 mg, 1.88 mmol) was addedat RT and the mixture then heated at 90° C. for 14 h. The product wasdetected by LCMS. Inorganic material was filtered off and the filtratewas purified by reverse phase chromatography to afford 10 mg of TFAsalt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.70-7.60 (d, 4H), 7.50-7.40 (t,3H), 7.30-7.20 (m, 1H), 6.90-6.80 (d, 1H), 3.80-3.70 (m, 2H), 3.50-3.40(m, 2H), 3.30-3.20 (d, 4H), 3.15 (s, 3H), 2.40 (s, 3H).

Example 130 Preparation of(E)-9-chloro-6-(3,4-difluorostyryl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 236)

2-(9-Chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(3,4-difluorophenyl)ethanol(150 mg, 0.384 mmol) was dissolved in DCM (10 mL), triethylamine (0.079mL, 0.576 mmol) was added and the mixture stirred for 10 min. Methanesulfonyl chloride (0.032 mL, 0.432 mmol) was added slowly at 0° C. andstirred at RT for 2 h. The reaction mixture was diluted with water andextracted with DCM. The organic layer was dried over anhydrous sodiumsulfate and evaporated under reduced pressure to obtain the crudeproduct. The crude mixture was dissolved in NMP (1.5 mL), KOH powder(150 mg, 2.68 mmol) was added at RT and the reaction mixture was heatedat 90° C. for 14 h. The product was detected by LCMS. Inorganic materialwas filtered off and the filtrate was purified by reverse phasechromatography to afford 5 mg of TFA salt. ¹H NMR (CD₃OD, TFA salt) δ(ppm): 7.70-7.50 (m, 4H), 7.30-7.10 (m, 3H), 6.90-6.70 (d, 1H),3.80-3.70 (m, 4H), 3.60-3.40 (m, 4H), 3.15 (s, 3H).

Example 131 Preparation of6-(2-fluorophenethyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 237)

2-(9-Chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluorophenyl)ethylmethanesulfonate (530 mg, 0.001177 mol) was dissolved in methanol and10% Pd—C (62 mg, 0.5885 mmol) was added. A drop of water was added andthe reaction mass is stirred at RT for 24 h under hydrogen atmosphere.The reaction mass was filtered through Celite and the filtrateconcentrated to obtain the crude compound. The crude was purified bypreparative HPLC to obtain 140 mg desired compound. ¹H NMR (CDCl₃, TFAsalt) δ (ppm): 7.60 (s, 1H), 7.30-7.20 (m, 2H), 7.20-7.15 (d, 1H),7.10-7.00 (t, 12H), 7.00-6.90 (t, 1H), 6.90-6.80 (t, 1H), 4.40-4.30 (t,2H), 3.90-3.85 (t, 2H), 3.60-3.50 (t, 2H), 3.30-3.10 (m, 4H), 3.10 (t,2H), 2.90 (s, 3H).

Example 132 Preparation of(E)-6-(2-(2,4-dichlorophenyl)prop-1-enyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 238)

3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1 mmol),1-(1-bromoprop-1-en-2-yl)-2,4-dichlorobenzene (318 mg, 1.2 mmol),L-proline (0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphatetribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged withnitrogen. The reaction mixture was heated at 85° C. overnight. Anadditional 1 eq. of reagents was added and the mixture heated for anadditional 24 h. The DMF was evaporated and the residue was poured intowater. The precipitate obtained was filtered and purified by silica gelchromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed byreverse phase HPLC to separate the isomers. ¹H NMR (CDCl₃, TFA salt) δ(ppm): 7.35 (s, 1H), 7.18 (m, 2H), 7.05 (d, 1H), 6.98 (d, 1H), 6.70 (m,2H), 3.60 (m, 2H), 3.10 (m, 5H), 2.90 (s, 3H), 2.60 (m, 1H), 2.42 (s,3H), 2.30 (s, 3H).

Example 133 Preparation of(E)-9-chloro-6-(2-(2,4-dichlorophenyl)prop-1-enyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 239)

9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1mmol), 1-(1-bromoprop-1-en-2-yl)-2,4-dichlorobenzene (318 mg, 1.2 mmol),L-proline (0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphatetribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged withnitrogen. The reaction mixture was heated at 85° C. overnight. Anadditional 1 eq. of reagents was added and the mixture heated for anadditional 24 h. The DMF was evaporated and the residue was poured intowater. The precipitate obtained was filtered and purified by silica gelchromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed byreverse phase HPLC to separate the isomers. ¹HNMR (CDCl₃, TFA salt) δ(ppm): 7.50 (d, 2H), 7.32 (m, 2H), 7.20 (s, 2H), 6.50 (s, 1H), 3.95 (m,2H), 3.60-3.20 (m, 6H), 3.05 (s, 3H), 1.80 (s, 3H).

Example 134 Preparation of(Z)-6-(2-(2-fluorophenyl)prop-1-enyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 240)

3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1 mmol),1-(1-bromoprop-1-en-2-yl)-2-fluorobenzene (260 mg, 1.2 mmol), L-proline(0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. Thereaction mixture was heated at 85° C. overnight. An additional 1 eq. ofreagents was added and the mixture heated for an additional 24 h. TheDMF was evaporated and the residue was poured into water. Theprecipitate obtained was filtered and purified by silica gelchromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed byreverse phase HPLC to separate the isomers. ¹HNMR (CDCl₃, TFA salt) δ(ppm): 7.15 (m, 3H), 7.05 (d, 1H), 6.95 (t, 1H), 6.85 (t, 1H), 6.75 (s,1H), 6.70 (d, 1H), 3.60 (m, 1H), 3.40 (m, 1H), 3.10 (m, 2H), 2.85 (m,2H), 2.80 (s, 3H), 2.42 (s, 3H), 2.33 (m, 2H), 2.30 (s, 3H).

Example 135 Preparation of(E)-6-(2-(2-fluorophenyl)prop-1-enyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 241)

3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1 mmol),1-(1-bromoprop-1-en-2-yl)-2-fluorobenzene (260 mg, 1.2 mmol), L-proline(0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. Thereaction mixture was heated at 85° C. overnight. An additional 1 eq. ofreagents was added and the mixture heated for an additional 24 h. TheDMF was evaporated and the residue was poured into water. Theprecipitate obtained was filtered and purified by silica gelchromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed byreverse phase HPLC to separate the isomers. ¹HNMR (CDCl₃, TFA salt) δ(ppm): 7.42 (m, 1H), 7.33 (m, 1H), 7.28 (s, 1H), 7.24 (d, 1H), 7.18 (dd,1H), 7.11 (d, 1H), 7.09 (d, 1H), 6.72 (s, 1H), 3.82 (m, 2H), 3.40 (m,1H), 3.30 (m, 5H), 3.0 (s, 3H), 2.45 (s, 3H), 1.90 (s, 3H).

Example 136 Preparation of(Z)-9-chloro-6-(2-(2-fluorophenyl)prop-1-enyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 242)

9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1mmol), 1-(1-bromoprop-1-en-2-yl)-2-fluorobenzene (260 mg, 1.2 mmol),L-proline (0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphatetribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged withnitrogen. The reaction mixture was heated at 85° C. overnight. Anadditional 1 eq. of reagents was added and the mixture heated for anadditional 24 h. The DMF was evaporated and the residue was poured intowater. The precipitate obtained was filtered and purified by silica gelchromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed byreverse phase HPLC to separate the isomers. ¹HNMR (CD₃OD, TFA salt) δ(ppm): 7.36 (d, 1H), 7.18 (m, 1H), 7.11 (s, 1H), 6.98 (dd, 1H), 6.92 (m,3H), 6.86 (s, 1H), 3.60 (m, 2H), 3.10 (m, 3H), 3.0 (s, 3H), 2.90 (m,3H), 2.30 (s, 3H).

Example 137 Preparation of(E)-9-chloro-6-(2-(2-fluorophenyl)prop-1-enyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 243)

9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1mmol), 1-(1-bromoprop-1-en-2-yl)-2-fluorobenzene (260 mg, 1.2 mmol),L-proline (0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphatetribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged withnitrogen. The reaction mixture was heated at 85° C. overnight. Anadditional 1 eq. of reagents was added and the mixture heated for anadditional 24 h. The DMF was evaporated and the residue was poured intowater. The precipitate obtained was filtered and purified by silica gelchromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed byreverse phase HPLC to separate the isomers. ¹HNMR (CD₃OD, TFA salt) δ(ppm): 7.56 (dd, 1H), 7.53 (s, 1H), 7.40 (m, 1H), 7.30 (d, 1H), 7.20 (m,3H), 6.80 (s, 1H), 3.80 (m, 2H), 3.40 (m, 3H), 3.30 (m, 2H), 3.15 (m,1H), 3.05 (s, 3H), 1.85 (s, 3H).

Example 138 Preparation of(Z)-9-chloro-6-(2-(2-chlorophenyl)prop-1-enyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 244)

9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234.72 mg,1 mmol), 1-(1-bromoprop-1-en-2-yl)-2-chlorobenzene (277.82 mg, 1.2mmol), L-proline (0.2 mmol), CuI (19 mg, 0.1 mmol) and potassiumphosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purgedwith nitrogen. The reaction mixture was heated at 85° C. overnight. Anadditional 1 eq. of reagents was added and the mixture heated for anadditional 24 h. The DMF was evaporated and the residue was poured intowater. The precipitate obtained was filtered and purified by silica gelchromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed byreverse phase HPLC to separate the isomers. ¹HNMR (CDCl₃, TFA salt) δ(ppm): 7.34 (m, 2H), 7.24 (d, 1H), 7.12 (d, 2H), 6.95 (m, 1H), 6.70 (m,2H), 3.60 (m, 1H), 3.50 (m, 1H), 3.25 (m, 2H), 3.10 (m, 2H), 3.0 (m,2H), 2.80 (s, 3H), 2.34 (s, 3H)

Example 139 Preparation of(E)-9-chloro-6-(2-(2-chlorophenyl)prop-1-enyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 245)

9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234.72 mg,1 mmol), 1-(1-bromoprop-1-en-2-yl)-2-chlorobenzene (277.82 mg, 1.2mmol), L-proline (0.2 mmol), CuI (19 mg, 0.1 mmol) and potassiumphosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purgedwith nitrogen. The reaction mixture was heated at 85° C. overnight. Anadditional 1 eq. of reagents was added and the mixture heated for anadditional 24 h. The DMF was evaporated and the residue was poured intowater. The precipitate obtained was filtered and purified by silica gelchromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed byreverse phase HPLC to separate the isomers. ¹HNMR (CDCl₃, TFA salt) δ(ppm): 7.50 (m, 2H), 7.35 (m, 2H), 7.20 (m, 3H), 6.50 (s, 1H), 3.90 (m,2H), 3.50 (m, 1H), 3.35 (m, 1H), 3.20 (m, 2H), 3.0 (s, 3H), 2.0 (m, 5H).

Example 140 Preparation of(E)-9-chloro-3-methyl-6-(2-(pyridin-3-yl)prop-1-enyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 246)

9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (200 mg,0.85 mmol) was dissolved in DMF (6 mL), CuI (16 mg, 0.085 mmol),L-proline (19 mg, 0.17 mmol), K₃PO₄ (364 mg, 1.70 mmol) were added andstirred for 10 min. at RT. 3-(1-Bromoprop-1-en-2-yl)pyridine (203 mg,1.02 mmol) was added dropwise and the reaction mixture was heated at 90°C. for 18 h. DMF was evaporated under reduced pressure and the reactionmixture was poured into water (10 mL). The aqueous mixture was extractedwith ethyl acetate. The organic layer was dried over Na₂SO₄, andconcentrated under reduced pressure to obtain the crude compound whichwas purified by column chromatography to 140 mg of the desired compound.¹NMR (CD₃OD, TFA salt) δ (ppm): 9.10 (s, 1H), 8.80 (s, 1H), 8.62 (d,1H), 7.90 (m, 1H), 7.60 (s, 1H), 7.38 (s, 1H), 7.20 (m, 2H), 3.80 (m,2H), 3.42 (m, 4H), 3.22 (m, 2H), 3.10 (s, 3H), 2.0 (s, 3H).

Example 141 Preparation of(E)-3,9-dimethyl-6-(2-(pyridin-3-yl)prop-1-enyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 247)

3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (200 mg, 0.934mmol) was dissolved in DMF (6 mL), CuI (17.7 mg, 0.09 mmol), L-proline(21 mg, 0.18 mmol), K₃PO₄ (397 mg, 1.86 mmol) was added and stirred for10 min. at RT. 3-(1-Bromoprop-1-en-2-yl)pyridine (222 mg, 1.12 mmol) wasadded dropwise and the reaction mixture was heated at 90° C. for 18 h.DMF was evaporated under reduced pressure, 10 mL water was added and themixture extracted with ethyl acetate. The organic layer was dried overNa₂SO₄, and concentrated under reduced pressure. The crude compound waspurified by column chromatography to 180 mg of the desired compound.¹HNMR (CD₃OD, TFA salt) δ (ppm): 9.10 (s, 1H), 8.80 (s, 1H), 8.70 (d,1H), 8.0 (t, 1H), 7.36 (s, 2H), 7.08 (m, 2H), 3.80 (m, 2H), 3.40 (m,4H), 3.20 (m, 2H), 3.05 (s, 3H), 2.42 (s, 3H), 1.05 (s, 3H).

Example 142 Preparation of(E)-9-chloro-3-methyl-6-(2-(pyridin-4-yl)prop-1-enyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 248)

A mixture of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(117 mg, 0.5 mmol) and potassium phosphate tribasic (212 mg, 1 mmol) inDMF was purged with nitrogen and heated at 90° C.4-(1-Bromoprop-1-en-2-yl)pyridine (107.83 mg, 0.55 mmol), L-proline(11.5 mg, 0.1 mmol), CuI (9.5 mg, 0.05 mmol) in DMF were charged in aseparate flask. This mixture was purged with nitrogen and heated at 90°C. for 5 min. Both reaction mixtures were combined and heated at 90° C.overnight. The reaction mixture was poured into water to obtain aprecipitate. The precipitate was filtered and purified with silicacolumn chromatography (100-200 mesh) by neutralizing the silica gel with2-3 drops of aq. NH₃ and using 0-2% MeOH:DCM as eluant. Compound wasfurther purified by reverse phase HPLC to obtain the product. ¹HNMR(CD₃OD, TFA salt) δ (ppm): 8.80 (d, 2H), 8.20 (d, 2H), 7.70 (d, 1H),7.58 (d, 1H), 7.20 (s, 2H), 3.70 (m, 2H), 3.40 (m, 2H), 3.30 (m, 4H),3.05 (s, 3H), 2.02 (s, 3H).

Example 143 Preparation of(Z)-9-chloro-6-(2-(3-fluorophenyl)prop-1-enyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 249)

A mixture of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(234 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-3-fluorobenzene (258 mg, 1.2mmol), L-proline (23 mg, 0.2 mmol), CuI (19 mg, 0.1 mmol) and potassiumphosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purgedwith nitrogen. The reaction mixture was heated at 85° C. overnight. Anadditional 1 eq. of reagents was added and the mixture heated for anadditional 24 h. The DMF was evaporated and the residue was poured intowater. The precipitate obtained was filtered and purified by silica gelchromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed byreverse phase HPLC to separate the isomers. ¹HNMR (CD₃OD, TFA salt) δ(ppm): 7.45 (s, 1H), 7.25 (d, 1H), 7.16 (m, 1H), 7.10 (m, 1H), 6.92 (t,1H), 6.82 (s, 1H), 6.62 (m, 2H), 3.60 (m, 1H), 3.50 (m, 1H), 3.30-3.0(m, 4H), 2.90 (s, 3H), 2.70 (m, 2H), 2.35 (s, 3H).

Example 144 Preparation of(E)-9-chloro-6-(2-(3-fluorophenyl)prop-1-enyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 250)

A mixture of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(234 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-3-fluorobenzene (258 mg, 1.2mmol), L-proline (23 mg, 0.2 mmol), CuI (19 mg, 0.1 mmol) and potassiumphosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purgedwith nitrogen. The reaction mixture was heated at 85° C. overnight. Anadditional 1 eq. of reagents was added and the mixture heated for anadditional 24 h. The DMF was evaporated and the residue was poured intowater. The precipitate obtained was filtered and purified by silica gelchromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed byreverse phase HPLC to separate the isomers. ¹HNMR (CD₃OD, TFA salt) δ(ppm): 7.58 (s, 1H), 7.42 (m, 3H), 7.15 (m, 3H), 7.05 (s, 1H), 3.80 (m,2H), 3.40 (m, 2H), 3.30 (m, 4H), 3.05 (s, 3H), 1.90 (s, 3H).

Example 145 Preparation of(Z)-6-(2-(3-fluorophenyl)prop-1-enyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 251)

A mixture of 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-3-fluorobenzene (258 mg, 1.2mmol), L-proline (23 mg, 0.2 mmol), CuI (19 mg, 0.1 mmol) and potassiumphosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purgedwith nitrogen. The reaction mixture was heated at 85° C. overnight. Anadditional 1 eq. of reagents was added and the mixture heated for anadditional 24 h. The DMF was evaporated and the residue was poured intowater. The precipitate obtained was filtered and purified by silica gelchromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed byreverse phase HPLC to separate the isomers. ¹HNMR (CD₃OD, TFA salt) δ(ppm): 7.30 (s, 1H), 7.16 (m, 2H), 7.0 (d, 1H), 6.92 (t, 1H), 6.85 (s,1H), 6.70 (d, 1H), 6.62 (d, 1H), 3.60 (m, 1H), 3.40 (m, 1H), 3.25 (m,1H), 3.10 (m, 1H), 2.95 (m, 2H), 2.90 (s, 3H), 2.70 (m, 2H), 2.42 (s,3H), 2.30 (s, 3H).

Example 146 Preparation of(E)-6-(2-(3-fluorophenyl)prop-1-enyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 252)

A mixture of 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-3-fluorobenzene (258 mg, 1.2mmol), L-proline (23 mg, 0.2 mmol), CuI (19 mg, 0.1 mmol) and potassiumphosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purgedwith nitrogen. The reaction mixture was heated at 85° C. overnight. Anadditional 1 eq. of reagents was added and the mixture heated for anadditional 24 h. The DMF was evaporated and the residue was poured intowater. The precipitate obtained was filtered and purified by silica gelchromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed byreverse phase HPLC to separate the isomers. ¹HNMR (CD₃OD, TFA salt) δ(ppm): 7.45 (m, 2H), 7.40 (d, 1H), 7.36 (s, 1H), 7.10 (m, 1H), 7.0 (m,3H), 3.80 (m, 2H), 3.40 (m, 2H), 3.20 (m, 4H), 3.05 (s, 3H), 2.42 (s,3H), 1.90 (s, 3H).

Example 147 Preparation of(E)-3,9-dimethyl-6-(2-(pyridin-4-yl)prop-1-enyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 253)

3,9-Dimethyl-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole (107.5 mg,0.5 mmol), potassium phosphate tribasic (212 mg, 1 mmol) in DMF and themixture purged with nitrogen. The reaction mass was heated at 85° C. for5 min. In another flask was added 4-(1-bromoprop-1-en-2-yl)pyridine(107.83 mg, 0.55 mmol), L-proline (11.5 mg, 0.1 mmol), CuI (9.5 mg, 0.05mmol) in DMF. This mixture was purged with nitrogen and heated at 90° C.for 5 min. The reaction mixtures were combined and heated at 90° C.overnight. The reaction mass was poured into water to obtain aprecipitate. The precipitate was filtered and purified with silicacolumn chromatography (100-200 mesh), by neutralizing the silica gelwith 2-3 drops of aq. ammonia and using 0-2% MeOH:DCM as eluant. Thecompound was further purified by reverse phase HPLC to obtain theproduct. ¹HNMR (CD₃OD, TFA salt) δ (ppm): 8.70 (d, 2H), 8.10 (d, 2H),7.62 (s, 1H), 7.38 (s, 1H), 7.05 (d, 2H), 3.80 (m, 2H), 3.40 (m, 2H),3.30 (m, 2H), 3.20 (m, 2H), 3.05 (s, 3H), 2.42 (s, 3H), 2.05 (s, 3H).

Example 148 Preparation of6-(4-fluorostyryl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole(Compound No. 39)

To a solution of2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-fluorophenyl)ethanol(150 mg, 0.42 mmol) in DCM (7 mL), triethylamine (0.088 mL, 0.63 mmol)was added and stirred for 10 min, methane sulfonyl chloride (0.036 mL,0.47 mmol) were added slowly at 0° C. and stirred at RT for 2 h.Reaction was monitored by TLC. The reaction mixture was diluted with DCMand washed with water. The organic layer was dried over anhydrous sodiumsulfate and evaporated under reduced pressure. Crude product wasdissolved in NMP (0.8 mL), KOH powder (166 mg, 2.97 mmol) was added atRT and heated at 90° C. for 14 h. Reaction was monitored by LCMS. Thereaction mixture was diluted with methanol, inorganic material wasfiltered off and the compound was purified by reverse phasechromatography to afford 10 mg of product as the TFA salt. ¹H NMR(CD₃OD, TFA salt) δ (ppm): 7.70-7.50 (m, 4H), 7.30 (s, 1H), 7.20-7.00(m, 3H), 6.80-6.70 (d, 1H), 3.90-3.75 (m, 4H), 3.50-3.40 (m, 4H), 3.15(s, 3H), 2.35 (s, 3H).

Example 149 Preparation of(Z)-9-chloro-6-(2-(2,4-dichlorophenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole(Compound No. 152)

9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol),L-proline (23 mg, 0.2 mmol) and K₃PO₄ (424 mg, 2 mmol) were added andthe reaction mixture was stirred for 10 min. at RT.141-Bromoprop-1-en-2-yl)-2,4-dichlorobenzene (318 mg, 1.2 mmol) wasadded dropwise and the reaction mixture was purged with nitrogen. Thereaction mixture was heated at 85° C. for overnight (prolonged heatingin some cases was required). The DMF was evaporated under reducedpressure, the residue was diluted with water and the solid was filtered.The solid material was purified by silica gel chromatography (100-200mesh) eluting with 0-5% methanol-dichloromethane. The product wasfurther purified by reverse phase HPLC. Yield: 8 mg. ¹HNMR (CDCl₃, TFAsalt) δ (ppm): 7.38 (s, 1H), 7.30 (s, 1H), 7.19 (d, 1H), 7.10 (d, 1H),6.95 (d, 1H), 6.70 (m, 2H), 3.70 (m, 2H), 3.10 (m, 4H), 2.90 (s, 3H),2.60 (m, 2H), 2.30 (s, 3H).

Example 150 Preparation of(E)-9-chloro-6-(2-(3,4-dichlorophenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole(Compound No. 154)9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (74 mg, 0.31mmol) was dissolved in DMF (5 mL). Copper (I) iodide (6 mg, 0.032 mmol),L-proline (7 mg, 0.063 mmol) and K₃PO₄ (134 mg, 0.63 mmol) were addedand the reaction mixture was stirred for 10 min. at RT.4-(1-Bromoprop-1-en-2-yl)-1,2-dichlorobenzene (100 mg, 0.378 mmol) wasadded dropwise and the reaction mixture was purged with nitrogen. Thereaction mixture was heated at 80° C. for overnight (prolonged heatingin some cases was required). The DMF was evaporated under reducedpressure, the residue was diluted with water and the solid was filtered.The solid material was purified by silica gel chromatography (100-200mesh). Yield: 74 mg. ¹HNMR (CD₃OD, TFA salt) δ (ppm): 7.82 (d, 1H), 7.62(d, 2H), 7.57 (s, 1H), 7.18 (d, 2H), 7.10 (d, 1H), 3.78 (m, 2H), 3.40(m, 4H), 3.20 (m, 2H), 3.06 (s, 3H), 1.90 (s, 3H). Example 151Preparation of(E)-9-chloro-6-(2-(3,4-difluorophenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole(Compound No. 155)9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (84 mg,0.359 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (8 mg, 0.035mmol), L-proline (9 mg, 0.086 mmol) and K₃PO₄ (183 mg, 0.862 mmol) wereadded and the reaction mixture was stirred for 10 min. at RT.4-(1-Bromoprop-1-en-2-yl)-1,2-difluorobenzene (100 mg, 0.431 mmol) wasadded dropwise and the reaction mixture was purged with nitrogen. Thereaction mixture was heated at 80° C. for overnight (prolonged heatingin some cases was required). The DMF was evaporated under reducedpressure, the residue was diluted with water and the solid was filtered.The solid material was purified by silica gel chromatography (100-200mesh). Yield: 55 mg. ¹HNMR (DMSO-d6, Oxalate salt) δ (ppm): 7.82 (m,1H), 7.62 (s, 1H), 7.55 (m, 2H), 7.20 (m, 2H), 7.12 (d, 1H), 3.38 (m,4H), 3.10 (m, 4H), 2.90 (s, 3H), 1.80 (s, 3H). Example 152 Preparationof(E)-9-chloro-6-(2-(3-fluoro-4-methoxyphenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole(Compound No. 157)9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (80 mg, 0.34mmol) was dissolved in DMF (6 mL). Copper (I) iodide (6 mg, 0.034 mmol),L-proline (8 mg, 0.068 mmol) and K₃PO₄ (145 mg, 0.68 mmol) were addedand the reaction mixture was stirred for 10 min. at RT.4-(1-Bromoprop-1-en-2-yl)-2-fluoro-1-methoxybenzene (100 mg, 0.34 mmol)was added dropwise and the reaction mixture was purged with nitrogen.The reaction mixture was heated at 80° C. for overnight (prolongedheating in some cases was required). The DMF was evaporated underreduced pressure, the residue was diluted with water and the solid wasfiltered. The solid material was purified by silica gel chromatography(100-200 mesh). Yield: 46 mg. ¹HNMR (CD₃OD, Oxalate salt) δ (ppm): 7.58(s, 1H), 7.42 (m, 2H), 7.16 (m, 3H), 6.95 (s, 1H), 3.90 (s, 3H), 3.60(m, 4H), 3.25 (m, 4H), 3.05 (s, 3H), 1.82 (s, 3H). Example 153Preparation of(E)-6-(3-fluoro-4-methoxystyryl)-9-chloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole(Compound No. 158)

To a solution of2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(3-fluoro-4-methoxyphenyl)ethanol(110 mg, 0.273 mmol) in DCM (5 mL), triethylamine (0.056 mL, 0.406 mmol)was added and stirred for 10 min., methane sulfonyl chloride (0.024 mL,0.03 mmol) was added slowly at 0° C. and stirred at RT for 2 h. Reactionmixture was diluted with water, extracted with dichloromethane. Theorganic layer was dried over anhydrous sodium sulfate and evaporatedunder reduced pressure. The crude product was dissolved in NMP (0.8 mL),KOH powder (105 mg, 1.8 mmol) was added at RT and heated at 90° C. for14 h. Product was detected by LCMS. Inorganic material was filtered offand the compound was purified by reverse phase chromatography to afford18 mg of TFA salt. ¹H NMR (DMSO-d6, TFA salt) δ (ppm): 7.80-7.60 (m,4H), 7.40-7.30 (d, 1H), 7.25-7.15 (t, 2H), 6.80-6.70 (d, 1H), 3.95 (s,3H), 3.70-3.60 (m, 4H), 3.00-2.90 (m, 4H), 2.45 (s, 3H).

Example 154 Preparation of(E)-9-chloro-1,2,3,4,5,6-hexahydro-6-(2-(4-methoxyphenyl)prop-1-enyl)-3-methylazepino[4,5-b]indole(Compound No. 160)

9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (43 mg,0.184 mmol) was dissolved in DMF (4 mL) Copper (I) iodide (4 mg, 0.0184mmol) L-proline (4.2 mg, 0.037 mmol) and K₃PO₄ (78 mg, 0.37 mmol) wereadded and the reaction mixture was stirred for 10 min. at RT.1-(1-Bromoprop-1-en-2-yl)-4-methoxybenzene (50 mg, 0.22 mmol) was addeddropwise and the reaction mixture was purged with nitrogen. The reactionmixture was heated at 80° C. for overnight (prolonged heating in somecases was required). The DMF was evaporated under reduced pressure, theresidue was diluted with water and the solid was filtered. The solidmaterial was purified by silica gel chromatography (100-200 mesh). ¹HNMR (DMSO-d6, Oxalate salt) δ (ppm): 7.60 (m, 3H), 7.10 (m, 2H), 6.98(m, 3H), 3.80 (s, 3H), 3.60 (m, 4H), 3.10 (m, 4H), 2.82 (s, 3H), 1.80(s, 3H).

Example 155 Preparation of(Z)-6-(2-(2,4-dichlorophenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole(Compound No. 174)

3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1 mmol)was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol), L-proline (23mg, 0.2 mmol) and K₃PO₄ (424 mg, 2 mmol) were added and the reactionmixture was stirred for 10 min at RT.1-(1-Bromoprop-1-en-2-yl)-2,4-dichlorobenzene (318 mg, 1.2 mmol) wasadded dropwise and the reaction mixture was purged with nitrogen. Thereaction mixture was heated at 85° C. for overnight (prolonged heatingin some cases was required). The DMF was evaporated under reducedpressure, the residue was diluted with water and the solid was filtered.The solid material was purified by silica gel chromatography (100-200mesh) eluting with 0-5% methanol-dichloromethane. The product wasfurther purified by reverse phase HPLC. Yield: 30 mg. ¹HNMR (CDCl₃, TFAsalt) δ (ppm): 7.50 (s, 1H), 7.38 (s, 2H), 7.28 (d, 1H), 7.18 (d, 1H),7.05 (d, 1H), 6.56 (s, 1H), 3.90 (m, 2H), 3.40 (m, 1H), 3.22 (m, 5H),3.0 (s, 3H), 2.42 (s, 3H), 1.82 (s, 3H)

Example 156 Preparation of(E)-6-(2-(3,4-dichlorophenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole(Compound No. 176)

3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (67 mg, 0.31mmol) was dissolved in DMF (5 mL). Copper (I) iodide (6 mg, 0.032 mmol),L-proline (7 mg, 0.063 mmol) and K₃PO₄ (134 mg, 0.63 mmol) were addedand the reaction mixture was stirred for 10 min at RT.4-(1-Bromoprop-1-en-2-yl)-1,2-dichlorobenzene (100 mg, 0.378 mmol) wasadded dropwise and the reaction mixture was purged with nitrogen. Thereaction mixture was heated at 80° C. for overnight (prolonged heatingin some cases was required). The DMF was evaporated under reducedpressure, the residue was diluted with water and the solid was filtered.The solid material was purified by silica gel chromatography (100-200mesh). Yield: 53 mg. ¹HNMR (CD₃OD, TFA salt) δ (ppm): 7.82 (s, 1H), 7.60(s, 2H), 7.36 (d, 1H), 7.10 (d, 1H), 7.0 (m, 2H), 3.78 (m, 2H), 3.40 (m,2H), 3.20 (m, 4H), 3.08 (s, 3H), 2.42 (s, 3H), 1.90 (s, 3H).

Example 157 Preparation of(E)-6-(2-(3,4-difluorophenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole(Compound No. 177)

3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (77 mg, 0.36mmol) was dissolved in DMF (6 mL). Copper (I) iodide (8 mg, 0.036 mmol),L-proline (9 mg, 0.086 mmol) and K₃PO₄ (183 mg, 0.86 mmol) were addedand the reaction mixture was stirred for 10 min at RT.4-(1-Bromoprop-1-en-2-yl)-1,2-difluorobenzene (100 mg, 0.43 mmol) wasadded dropwise and the reaction mixture was purged with nitrogen. Thereaction mixture was heated at 80° C. for overnight (prolonged heatingin some cases was required). The DMF was evaporated under reducedpressure, the residue was diluted with water and the solid was filtered.The solid material was purified by silica gel chromatography (100-200mesh). Yield: 52 mg. ¹HNMR (CD₃OD, Oxalate salt) δ (ppm): 7.60 (m, 1H),7.50 (m, 1H), 7.30 (m, 2H), 7.0 (s, 3H), 3.60 (m, 4H), 3.25 (m, 4H),3.05 (s, 3H), 2.42 (s, 3H), 1.90 (s, 3H).

Example 158 Preparation of(E)-6-(2-(3-fluoro-4-methoxyphenyl)prop-1-enyl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole(Compound No. 179)

3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (73 mg, 0.34mmol) was dissolved in DMF (6 mL). Copper (I) iodide (6 mg, 0.034 mmol),L-proline (8 mg, 0.068 mmol) and K₃PO₄ (145 mg, 0.68 mmol) were addedand the reaction mixture was stirred for 10 min at RT.4-(1-Bromoprop-1-en-2-yl)-2-fluoro-1-methoxybenzene (100 mg, 0.34 mmol)was added dropwise and the reaction mixture was purged with nitrogen.The reaction mixture was heated at 80° C. for overnight (prolongedheating in some cases was required). The DMF was evaporated underreduced pressure, the residue was diluted with water and the solid wasfiltered. The solid material was purified by silica gel chromatography(100-200 mesh). Yield: 70 mg. ¹HNMR (CD₃OD, Oxalate salt) δ (ppm): 7.42(s, 1H), 7.40 (d, 1H), 7.30 (s, 1H), 7.15 (t, 1H), 7.02 (m, 2H), 6.96(s, 1H), 3.90 (s, 3H), 3.60 (m, 4H), 3.22 (m, 4H), 3.05 (s, 3H), 2.40(s, 3H), 1.82 (s, 3H).

Example 159 Preparation of(E)-6-(3-fluoro-4-methoxystyryl)-1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole(Compound No. 180)

To a solution of2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(3-fluoro-4-methoxyphenyl)ethanol(160 mg, 0.04 mmol) in DCM (7 mL), triethylamine (0.087 mL, 0.082 mmol)were added and stirred for 10 min., methane sulfonyl chloride (0.022 mL,0.035 mmol) was added slowly at 0° C. and stirred at RT for 2 h.Reaction mixture was diluted with water, extracted with dichloromethane.The organic layer was dried over anhydrous sodium sulfate and evaporatedunder reduced pressure. The crude product was dissolved in NMP (0.8 mL),KOH powder (164 mg, 2.93 mmol) was added at RT and heated at 90° C. for14 h. Product was detected by LCMS. Inorganic material was filtered offand the compound was purified by reverse phase chromatography to afford38 mg of TFA salt. ¹H NMR (DMSO-d6, TFA salt) δ (ppm): 7.80-7.60 (m,3H), 7.50-7.30 (m, 2H), 7.30-7.20 (t, 1H), 7.10-7.00 (d, 1H), 6.80-6.70(d, 1H), 3.95 (s, 3H), 3.85-3.80 (m, 4H), 3.00-2.80 (m, 2H), 2.95 (s,3H), 2.45 (s, 2H), 2.38 (s, 3H).

Example 160 Preparation of(E)-1,2,3,4,5,6-hexahydro-6-(2-(4-methoxyphenyl)prop-1-enyl)-3,9-dimethylazepino[4,5-b]indole(Compound No. 182)

3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (78 mg, 0.36mmol) was dissolved in DMF (5 mL) Copper (I) iodide (7 mg, 0.036 mmol)L-proline (8 mg, 0.073 mmol) and K₃PO₄ (156 mg, 0.734 mmol) were addedand the reaction mixture was stirred for 10 min at RT.1-(1-Bromoprop-1-en-2-yl)-4-methoxybenzene (100 mg, 0.44 mmol) was addeddropwise and the reaction mixture was purged with nitrogen. The reactionmixture was heated at 80° C. for overnight (prolonged heating in somecases was required). The DMF was evaporated under reduced pressure, theresidue was diluted with water and the solid was filtered. The solidmaterial was purified by silica gel chromatography (100-200 mesh). ¹HNMR(DMSO-d6, Oxalate salt) δ (ppm): 7.62 (d, 2H), 7.30 (s, 1H), 7.0 (m,4H), 6.95 (d, 1H), 3.80 (s, 3H), 3.40 (m, 4H), 3.10 (m, 4H), 2.80 (s,3H), 2.40 (s, 3H), 1.82 (s, 3H).

Example 161 Preparation of2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(piperazin-1-yl)ethanone(Compound No. 224)

To a solution of sodium hydride (46 mg, 1.16 mmol) in THF (5 ml),3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.1 g, 0.46mmol) was added at 0° C. and stirred at RT for 30 min. tert-Butyl4-(2-chloroacetyl)piperazine-1-carboxylate (147 mg, 0.55 mmol) was addedslowly dropwise at RT and stirred for 2 h at RT. After completion of thereaction (monitored by TLC & LCMS), the reaction was quenched with icewater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate and evaporated underreduced pressure. Crude product was purified by column chromatography toafford free base, which was converted to HCl salt using ethanolic HCl(38 mg). The NMR confirmed removal of the Boc group when ethanolic HClwas used. ¹H NMR (CD₃OD, DiHCl salt) δ (ppm): 7.3 (s, 1H), 7.22 (d, 1H),7.0 (d, 1H), 5.23 (d, 2H), 3.95-4.10 (m, 4H), 3.7-3.9 (m, 4H), 3.36-3.43(m, 4H), 3.1-3.22 (m, 4H), 3.0 (s, 3H), 2.4 (s, 3H).

Example 162 Preparation of2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-methylpiperidin-1-yl)ethanone(Compound No. 225)

To a solution of sodium hydride (46 mg, 1.16 mmol) in THF (5 ml),3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.1 g, 0.46mmol) was added at 0° C. and stirred at RT for 30 min.2-Chloro-1-(4-methylpiperidin-1-yl)ethanone (98 mg, 0.55 mmol) was addedslowly dropwise at RT and stirred for 2 h at RT. After completion of thereaction (monitored by TLC & LCMS), the reaction was quenched with icewater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate and evaporated underreduced pressure. The crude product was purified by columnchromatography to afford free base, which was converted to HCl saltusing ethanolic HCl. ¹H NMR (DMSO-d6, HCl salt) δ (ppm): 11.22 (bs, 1H),7.20 (m, 2H), 5.0-5.20 (m, 2H), 4.23 (d, 1H), 4.0 (d, 1H), 3.5-3.6 (m,2H), 3.0-3.23 (m, 4H), 2.8-2.95 (m, 2H), 2.26-2.42 (m, 2H), 1.5-1.8 (m,3H), 1.09-1.2 (m, 1H), 0.96 (d, 3H).

Example 163 Preparation of(E)-9-chloro-6-(3,4-dimethoxystyryl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 226)

To a solution of2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(3,4-dimethoxyphenyl)ethanol(300 mg, 0.722 mmol) in DCM (5 mL), triethylamine (0.15 mL, 1.077 mmol)were added and stirred for 10 min., methane sulfonyl chloride (0.062 mL,0.795 mmol) was added slowly at 0° C. and stirred at the sametemperature for 1 h, then at RT for 2 h. Reaction mixture was dilutedwith water, extracted with dichloromethane. The organic layer was driedover anhydrous sodium sulfate and evaporated under reduced pressure. Thecrude product was purified by column chromatography. The pure productwas dissolved in NMP (2.0 mL), KOH powder (283 mg, 5.06 mmol) was addedat RT and heated at 90° C. for 14 h. Product was detected by LCMS. Thereaction mixture was diluted with methanol, filtered and evaporated.Crude product was purified by reverse phase chromatography to get 18 mgof pure product as TFA salt. ¹H NMR (DMSO-d6, TFA salt) δ (ppm):7.80-7.60 (m, 2H), 7.35 (s, 1H), 7.30-7.20 (d, 1H), 7.20-7.15 (d, 1H),7.00-6.90 (d, 1H), 6.80-6.70 (m, 2H), 3.90 (s, 3H), 3.85 (s, 3H),3.80-3.60 (m, 2H), 2.95 (s, 3H), 2.90-2.80 (m, 2H), 2.60-2.30 (m, 4H).

Example 164 Preparation of1-(3,4-dimethoxyphenyl)-2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethanol(Compound No. 227)

3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (500 mg, 2.33mmol) was dissolved in DMF (6 ml). A solution of sodium hydride (50%)(168 mg, 7.00 mmol) was added in portions at RT and stirred at RT for 10min. A solution of 2-(3,4-dimethoxyphenyl)oxirane (630 mg, 3.50 mmol) inDMF (4 ml) was added dropwise for 10 min and stirred for 14 h at RT.Reaction was monitored by LCMS. The reaction mixture was quenched withice water, extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate and evaporated underreduced pressure. The crude product was purified by columnchromatography to get 50 mg of pure product. ¹H NMR (CDCl₃, Oxalatesalt) δ (ppm): 7.40-7.30 (m, 2H), 7.10-7.00 (m, 1H), 6.90-6.80 (t, 2H),6.80-6.60 (t, 1H), 5.00-4.80 (t, 2H), 4.30-4.20 (m, 2H), 3.95 (s, 3H),3.80 (s, 3H), 3.00-2.90 (m, 4H), 2.80 (s, 3H), 2.75-2.70 (m, 2H), 2.35(s, 3H).

Example 165 Preparation of(E)-9-chloro-3-methyl-6-styryl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 228)

To a solution of2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-phenylethanol(100 mg, 0.28 mmol) in DCM (6 mL), triethylamine (0.06 mL, 0.42 mmol)was added and stirred for 10 min., methane sulfonyl chloride (0.024 mL,0.31 mmol) was added slowly at 0° C. and stirred at RT for 2 h. Reactionwas monitored by TLC. Reaction mixture was diluted with DCM washed withwater. Organic layer was dried over anhydrous sodium sulfate andevaporated under reduced pressure. Crude product was dissolved in NMP(0.7 mL), KOH powder (158 mg, 2.82 mmol) was added at RT and heated at90° C. for 14 h. Reaction was monitored by LCMS. The reaction mixturewas diluted with methanol, inorganic material was filtered off and thecompound was purified by reverse phase chromatography to afford 8 mg ofTFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.70-7.60 (m, 5H), 7.50-7.40(t, 2H), 7.30-7.20 (d, 1H), 7.22-7.10 (d, 1H), 6.90-6.80 (d, 1H),3.85-3.75 (m, 4H), 3.45-3.40 (m, 4H), 3.15 (s, 3H).

Example 166 Preparation of(E)-3,9-dimethyl-6-styryl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 229)

To a solution of2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-phenylethanol(100 mg, 0.299 mmol) in DCM (2 mL), triethylamine (0.062 mL, 0.44 mmol)was added and stirred for 10 min., methane sulfonyl chloride (0.025 mL,0.32 mmol) was added slowly at 0° C. and stirred at RT for 2 h. Reactionwas monitored by TLC. The reaction mixture was diluted with DCM washedwith water. The organic layer was dried over anhydrous sodium sulfateand evaporated under reduced pressure. Crude product was dissolved inNMP (0.7 mL), KOH powder (117 mg, 2.09 mmol) was added at RT and heatedat 90° C. for 14 h. Reaction was monitored by LCMS. The reaction mixturewas diluted with methanol, inorganic material was filtered off and thecompound was purified by reverse phase chromatography to afford 20 mg ofTFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.70-7.50 (m, 5H), 7.40-7.20(m, 3H), 7.15-7.00 (d, 1H), 6.80-6.70 (d, 1H), 3.90-3.80 (t, 2H),3.60-3.50 (m, 4H), 3.35-3.20 (t, 2H), 3.15 (s, 3H), 2.40 (s, 3H).

Example 167 Preparation of(E)-6-(2-fluoro-4-methoxystyryl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 230)

To a solution of2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluoro-4-methoxyphenyl)ethanol(200 mg, 0.52 mmol) in DCM (10 mL), triethylamine (0.11 mL, 0.78 mmol)was added and stirred for 10 min., methane sulfonyl chloride (0.044 mL,0.56 mmol) was added slowly at 0° C. and stirred at RT for 2 h. Reactionwas monitored by TLC. The reaction mixture was diluted with DCM andwashed with water. The organic layer was dried over anhydrous sodiumsulfate and evaporated under reduced pressure. The crude product wasdissolved in NMP (0.8 mL), KOH powder (205 mg, 3.66 mmol) was added atRT and heated at 90° C. for 14 h. Reaction was monitored by LCMS. Thereaction mixture was diluted with methanol, inorganic material wasfiltered off and the compound was purified by reverse phasechromatography to afford 25 mg of TFA salt. ¹H NMR (CD₃OD, TFA salt) δ(ppm): 7.70-7.60 (m, 2H), 7.60-7.50 (m, 1H), 7.40-7.30 (m, 1H),7.30-7.25 (m, 1H), 7.18-7.10 (d, 1H), 6.90-6.80 (m, 2H), 3.80 (s, 3H),3.60-3.50 (m, 4H), 3.40-3.30 (m, 4H), 3.15 (s, 3H), 2.41 (s, 3H).

Example 168 Preparation of(E)-3,9-dimethyl-6-(2-(pyrimidin-4-yl)prop-1-enyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 254)

4-(1-bromoprop-1-en-2-yl)pyrimidine (236 mg, 1.2 mmol) was dissolved inDMF (5 mL) and was added K₃PO₄ (424 mg, 2 mmol) followed by the additionof Copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol).1, 2, 3, 4, 5, 6-hexahydro-3,9-dimethylazepino[4, 5-b]indole (214 mg, 1mmol) was added and purged nitrogen for 2 min. Reaction mass was stirredat 85 degree C. for overnight. Water was added and filtered the solidmass under vacuum. Crude was purified on silica gel (100-200 mesh) using0-10% methanol: dichloromethane as eluent. Yield: 72 mg. ¹H NMR (CDCl₃,Oxalate salt) δ (ppm): 9.20 (s, 1H), 8.76 (s, 1H), 8.0 (s, 1H), 7.44 (d,1H), 7.30 (s, 1H), 7.0 (s, 2H), 2.99 (m, 4H), 2.84 (m, 4H), 2.50 (s,3H), 2.42 (s, 3H), 2.04 (s, 3H).

Example 169 Preparation of9-chloro-6-((4-fluorophenyl)ethynyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 281)

9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg,μmol) was dissolved in toluene (4 mL) and the reaction mixture stirredfor 10 min. K₂CO₃ (276 mg, 0.2 mmol), CuSO₄.5H₂O (249 mg, 0.01 mmol) and1,10-Phenanthroline (36 mg, 0.2 mmol) were added to the reaction mixtureand again stirred for 10 min. 1-(Bromoethynyl)-4-fluorobenzene (220 mg,1.1 mmol) in toluene (2 mL) was added and reaction mixture was heated at80-85° C. overnight. Toluene was evaporated under reduced pressure toobtain the crude compound. The crude was purified by silica gel (100-200mesh) column chromatography using 0-100% Hexane:Ethyl acetate as eluentfollowed by reverse phase chromatography to obtain the product as TFAsalt. ¹H NMR CD₃OD, TFA salt) δ (ppm): 7.60 (m, 2H), 7.30 (m, 2H), 7.18(m, 2H), 7.08 (m, 1H), 3.60 (m, 4H), 3.46 (m, 2H), 3.20 (m, 2H), 3.05(s, 3H)

Example 170 Preparation of9-chloro-6-((4-chlorophenyl)ethynyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 282)

A mixture of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(235 mg, 1 mmol), CuSO₄.5H₂O (50 mg, 0.2 mmol), 1,10-Phenanthroline (72mg, 0.4 mmol), K₃PO₄ (425 mg, 2 mmol) and1-(bromoethynyl)-4-chlorobenzene (237 mg, 1.1 mmol) in toluene (10 mL)was flushed with nitrogen heated 80° C. for 16 h. The reaction wasmonitored by LCMS. The reaction mixture was filtered through Celite,washed with DCM. The organic layer was concentrated and purified bycolumn chromatography (silica gel, 60-80% ethyl acetate in hexane) toget 37 mg of product. ¹H NMR (CDCl₃, HCl salt) δ (ppm): 7.50 (s, 1H)7.49-7.40 (m, 3H), 7.38-7.32 (m, 2H), 7.25-7.20 (d, 1H), 3.22-3.18 (m,2H), 3.0-2.90 (m, 6H), 2.60 (s, 3H).

Example 171 Preparation of9-chloro-6-((3-fluoro-4-methoxyphenyl)ethynyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 283)

9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg,0.42 mmol), CuSO₄.5H₂O (21 mg, 0.085 mmol), 1,10-Phenanthroline (30 mg,0.17 mmol) and K₃PO₄ (180 mg, 0.85 mmol) and4-(bromoethynyl)-2-fluoro-1-methoxybenzene (131 mg, 0.46 mmol) intoluene (5 mL) were charged and flushed with nitrogen. The reactionmixture was heated at 80° C. for 16 h. The reaction was monitored byLCMS. The reaction mixture was filtered through Celite, washed with DCM.The organic layer was concentrated and purified by column chromatography(100-200 mesh size silica gel, 60-80% ethyl acetate in hexane) to get9-chloro-6-((3-fluoro-4-methoxyphenyl)ethynyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolewhich was further purified by prep TLC to get 24 mg of product. ¹HNMR(CDCl₃, freebase) δ (ppm): 7.40 (d, 2H), 7.30 (m, 2H), 7.20 (d, 1H),6.95 (t, 1H), 3.90 (s, 3H), 3.10 (m, 2H), 2.90 (m, 6H), 2.50 (s, 3H).

Example 172 Preparation of6-((3-fluoro-4-methoxyphenyl)ethynyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Compound No. 284)

3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46mmol), CuSO₄.5H₂O (23 mg, 0.093 mmol), 1,10-Phenanthroline (33 mg, 0.18mmol) and K₃PO₄ (197 mg, 0.93 mmol) and4-(bromoethynyl)-2-fluoro-1-methoxybenzene (116 mg, 0.51 mmol) intoluene (5 mL) were added and flushed with nitrogen. The reactionmixture was heated at 80° C. for 16 h. The reaction was monitored byLCMS. The reaction mixture was filtered through Celite, washed with DCM.The organic layer was concentrated and purified by column chromatography(100-200 mesh size silica gel, 60-80% ethyl acetate in hexane) to get6-((3-fluoro-4-methoxyphenyl)ethynyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolewhich was repurified by prep TLC to get 8 mg product as brown solid.¹HNMR (CDCl₃, freebase) δ (ppm): 7.40 (d, 1H), 7.22 (m, 3H), 7.10 (d,1H), 6.95 (t, 1H), 3.90 (s, 3H), 3.15 (m, 2H), 2.90 (m, 6H), 2.50 (s,3H), 2.42 (s, 3H).

Example 173 Preparation of1-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(4-fluorophenyl)ethanone(Compound No. 285)

3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 10 mmol)was dissolved in toluene (3 mL) and stirred for 10 min. K₂CO₃ (276 mg,0.2 mmol), CuSO₄.5H₂O (249 mg, 0.01 mmol) and 1,10-Phenanthraline (36mg, 0.2 mmol) were added to the reaction mixture and stirred at RT for10 min. 1-(Bromoethynyl)-4-fluorobenzene (220 mg, 1.1 mmol) in toluene(2 mL) was added and the reaction mixture was heated to 80-85° C.overnight. The toluene was evaporated under reduced pressure to obtainthe crude product. The crude product was purified by silica gel (100-200mesh) column chromatography using 0-5% MeOH in dichloromethane as eluentfollowed by reverse phase chromatography to obtain the product as TFAsalt. ¹HNMR (CD₃OD, TFA salt) δ (ppm): 7.65 (m, 2H), 7.55 (m, 2H), 7.30(m, 2H), 7.20 (m, 2H), 7.05 (m, 1H), 3.60 (m, 5H), 3.45 (m, 3H), 3.20(m, 3H), 3.0 (s, 3H).

Example 174 Preparation of(E)-9-chloro-6-(2-fluorostyryl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 83)

To a solution of2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluorophenyl)ethanol(100 mg, 0.26 mmol) in DCM (2.5 mL), triethylamine (0.055 mL, 0.04 mmol)was added and stirred for 10 min, methanesulfonyl chloride (0.022 mL,0.029 mmol) was added slowly at 0° C. and stirred at RT for 2 h.Reaction mixture was diluted with water, extracted with dichloromethane.Organic layer was dried over anhydrous sodium sulfate and evaporatedunder reduced pressure. Crude product was taken in NMP (0.7 mL), KOHpowder (105 mg, 1.8 mmol) was added at RT and heated at 90° C. for 14 h.The compound was purified by reverse phase chromatography to afford 9 mgof TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.80-7.70 (m, 2H),7.60-7.50 (m, 2H), 7.35-7.25 (m, 1H), 7.20-7.10 (m, 3H), 6.90-6.80 (d,1H), 3.90-3.80 (m, 4H), 3.60-3.50 (m, 4H), 3.15 (s, 3H).

Example 175 Preparation of(E)-9-chloro-6-(2-fluorostyryl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Compound No. 286)

4-(1-bromoprop-1-en-2-yl)pyrimidine (197 mg, 1 mmol) was dissolved inDMF (5 mL). To this solution was added K₃PO₄ (424 mg, 2 mmol) followedby copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol).9-Chloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole (234 mg, 1mmol) was then added and the reaction mixture was purged with nitrogenfor 2 min. The reaction mixture was stirred at 85° C. overnight. Waterwas added and the product was extracted with ethyl acetate. Solvent wasremoved under reduced pressure and the residue was purified by silicagel chromatography (100-200 mesh) using 0-10% MeOH: DCM as eluent. Thecompound was further purified through reverse phase chromatography.Yield: 33 mg. ¹H NMR (CD₃OD, Oxalate salt) δ (ppm): 9.18 (s, 1H), 8.81(d, 1H), 8.0 (s, 1H), 7.80 (d, 1H), 7.60 (s, 1H), 7.18 (m, 2H), 3.60 (m,4H), 3.30 (m, 4H), 3.10 (s, 3H), 2.0 (s, 3H).

Example B1 Determination of the Ability of Compounds of the Invention toBind a Histamine Receptor Histamine H1

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant histamine H1 receptor expressed inChinese hamster ovary (CHO) cells (De Backer, M. D. et al., Biochem.Biophys. Res. Comm. 197(3):1601, 1993) in a modified Tris-HCl buffer (50mM Tris-HCl, pH 7.4, 2 mM MgCl₂, 100 mM NaCl, 250 mM Sucrose) was used.Compounds of the invention were incubated with 1.2 nM [³H]Pyrilamine for180 min. at 25° C. Non-specific binding was estimated in the presence of1 μM pyrilamine. Receptor proteins were filtered and washed, the filterswere then counted to determine [³H]Pyrilamine specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Biochemical assay results are presented as the percent inhibition ofspecific binding in Table 6.

Histamine H2

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant histamine H2 receptor expressed inChinese hamster ovary (CHO) K₁ cells (Ruat, M., Proc. Natl. Acad. Sci.USA. 87(5):1658, 1990) in a 50 mM Phosphate buffer, pH 7.4 was used.Compounds of the invention were incubated with 0.1 nM[¹²⁵I]Aminopotentidine for 120 min. at 25° C. Non-specific binding wasestimated in the presence of 3 μM Tiotidine. Receptor proteins werefiltered and washed, the filters were then counted to determine[¹²⁵I]Aminopotentidine specifically bound. Compounds were screened at 1μM or lower, using 1% DMSO as vehicle. Biochemical assay results arepresented as the percent inhibition of specific binding in Table 6.

Histamine H3

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant histamine H₃ receptor expressed inChinese hamster ovary (CHO—K1) cells (Yanai K et al. Jpn J. Pharmacol.65(2): 107, 1994; Zhu Y et al. Mol. Pharmacol. 59(3): 434, 2001) in amodified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 5 mM MgCl₂, 0.04% BSA)is used. Compounds of invention are incubated with 3 nM[³H]R(−)-α-Methylhistamine for 90 min. at 25° C. Non-specific binding isestimated in the presence of 1 μM R(−)-α-Methylhistamine. Receptorproteins are filtered and washed, the filters are counted to determine[³H]R(−)-α-Methylhistamine specifically bound. Compounds are screened at1 μM or lower, using 1% DMSO as vehicle. Compounds of the invention aretested in this biochemical assay and percent inhibition of specificbinding is determined.

Example B2 Determination of the Ability of Compounds of the Invention toBind a Imidazoline I₂ Receptor Central Imidazoline I₂

To evaluate in radioligand binding assays the activity of compounds ofthe invention, rat central imidazoline I₂ receptor obtained from WistarRat cerebral cortex (Brown, C. M. et al., Br. J. Pharmacol. 99:803,1990) in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5mM EDTA) is used. Compounds of the invention are incubated with 2 nM[³H]Idazoxan for 30 min. at 25° C. Non-specific binding is estimated inthe presence of 1 μM Idazoxan. Receptor proteins are filtered andwashed, the filters are counted to determine [³H]Idazoxan specificallybound. Compounds are screened at 1 μM or lower, using 1% DMSO asvehicle. Compounds of the invention are tested in this biochemical assayand percent inhibition of specific binding is determined.

TABLE 4 Binding data Histamine Binding Compound (1 μM) No. H1 H2 1 96 582 93 105 3 102 82 4 100 59 5 100 62 6 103 52 7 101 52 8 97 68 9 99 44 10101 78 11 97 7 12 99 98 13 98 92 14 98 83 15 100 92 16 103 92 17 101 8418 98 51 19 99 42 20 99 37 21 96 13 22 12 5 23 58 −3 24 100 58 25 91 4726 97 84 27 101 78 28 103 97 29 98 105 30 102 97 31 14 −10 32 11 −5 3387 101 34 95 103 35 100 104 36 88 104 37 13 4 38 83 26 39 98 91 40 10161 41 100 52 42 103 45 43 100 30 44 16 1 45 13 7 46 108 89 47 100 70 4898 56 49 94 65 50 98 65 51 102 70 52 96 61 53 14 3 54 18 −3 55 15 −3 56105 74 57 8 1 58 98 91 59 60 37 60 2 6 61 97 89 62 98 79 63 99 83 67 10072 68 102 69 69 2 −9 72 −12 0 73 18 −5 74 25 9 75 20 −4 76 95 19 77 9737 78 100 91 79 6 0 82 103 95 83 97 98 152 91 86 154 94 97 155 93 92 15768 93 158 98 89 160 87 91 174 98 99 176 82 95 177 93 92 179 45 88 180 9777 182 62 92 224 33 −4 225 95 6 226 99 39 227 95 19 228 99 97 229 100 94230 95 89 232 95 22 233 98 94 234 99 92 235 97 94 236 99 97 237 96 81238 98 98 239 91 89 240 96 87 241 98 93 242 100 98 243 93 84 244 102 99245 96 88 246 96 48 247 82 36 248 88 44 249 98 97 250 93 85 251 96 95252 93 87 253 32 31 281 56 76 282 99 87 283 12 83 284 11 4 285 68 74

Example B3 Determination of the Ability of Compounds of the Invention toBind an Adrenergic Receptor Adrenergic α_(1A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, rat adrenergic α_(1A) receptor obtained from Wistar Ratsubmaxillary glands (Michel, A. D. et al., Br. J. Pharmacol. 98:883,1989) in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5mM EDTA) is used. Compounds of the invention are incubated with 0.25 nM[³H]Prozosin for 60 min. at 25° C. Non-specific binding is estimated inthe presence of 10 μM phentolamine. Receptor proteins are filtered andwashed, the filters are counted to determine [³H]Prozosin specificallybound. Compounds of the invention are screened at 1 μM or lower, using1% DMSO as vehicle. Compounds of the invention are tested in thisbiochemical assay and percent inhibition of specific binding isdetermined.

Adrenergic α_(1B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, rat adrenergic α_(1B) receptor obtained from Wistar Ratliver (Garcia-S'ainz, J. A. et al., Biochem. Biophys. Res. Commun.186:760, 1992; Michel A. D. et al., Br. J. Pharmacol. 98:883, 1989) in amodified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mM EDTA) isused. Compounds of the invention are incubated with 0.25 nM [³H]Prozosinfor 60 min. at 25° C. Non-specific binding is estimated in the presenceof 10 μM phentolamine. Receptor proteins are filtered and washed, thefilters are counted to determine [³H]Prozosin specifically bound.Compounds are screened at 1 μM or lower, using 1% DMSO as vehicle.Compounds of the invention are tested in this biochemical assay andpercent inhibition of specific binding is determined.

Adrenergic α_(1D)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(1D) receptor expressed inhuman embryonic kidney (HEK-293) cells (Kenny, B. A. et al. Br. J.Pharmacol. 115(6):981, 1995) in a 50 mM Tris-HCl buffer, pH 7.4, wasused. Compounds of invention were incubated with 0.6 nM [³H]Prozosin for60 min. at 25° C. Non-specific binding was estimated in the presence of10 μM phentolamine. Receptor proteins were filtered and washed, thefilters were then counted to determine [³H]Prozosin specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Biochemical assay results are presented as the percent inhibition ofspecific binding in Table 5.

Adrenergic α_(2A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(2A) receptor expressed ininsect Sf9 cells (Uhlen S et al. J Pharmacol Exp Ther. 271:1558, 1994)in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mM MgCl₂, 2mM EDTA) was used. Compounds of invention were incubated with 1 nM[³H]MK-912 for 60 min. at 25° C. MK912 is(2S-trans)-1,3,4,5′,6,6′,7,12b-octahydro-1′,3′-dimethyl-spiro[2h-benzofuro[2,3-a]quinolizine-2,4′(1′H)-pyrimidin]-2′(3′H)-onehydrochloride Non-specific binding was estimated in the presence of 10μM WB-4101 (2-(2,6-Dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxanehydrochloride). Receptor proteins were filtered and washed, the filterswere then counted to determine [³H]MK-912 specifically bound. Compoundswere screened at 1 μM or lower, using 1% DMSO as vehicle. Biochemicalassay results are presented as the percent inhibition of specificbinding in Table 5.

Adrenergic α_(2B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(2B) receptor expressed inChinese hamster ovary (CHO—K1) cells (Uhlen S et al. Eur J. Pharmacol.343(1):93, 1998) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4,12.5 mM MgCl₂, 1 mM EDTA, 0.2% BSA) was used. Compounds of the inventionwere incubated with 2.5 nM [³H]Rauwolscine for 60 min. at 25° C.Non-specific binding was estimated in the presence of 10 μM Prozosin.Receptor proteins were filtered and washed, the filters were thencounted to determine [³H]Rauwolscine specifically bound. Compounds werescreened at 1 μM or lower, using 1% DMSO as vehicle. Biochemical assayresults are presented as the percent inhibition of specific binding inTable 5.

Adrenergic α_(2C)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(2C) receptor expressed ininsect Sf9 cells (Uhlen S et al. J Pharmacol Exp Ther. 271:1558, 1994)in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mM MgCl₂, 2mM EDTA) is used. Compounds of the invention are incubated with 1 nM[³H]MK-912 for 60 min. at 25° C. Non-specific binding is estimated inthe presence of 10 μM WB-4101. Receptor proteins are filtered andwashed, the filters are counted to determine [³H]MK-912 specificallybound. Compounds are screened at 1 μM or lower, using 1% DMSO asvehicle. Compounds of the invention are tested in this biochemical assayand percent inhibition of specific binding is determined.

Example B4 Determination of the Ability of Compounds of the Invention toBind a Dopamine Receptor Dopamine D_(2L)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant dopamine D_(2L) receptor expressed inChinese hamster ovary (CHO) cells (Grandy, D. K. et al. Proc. Natl.Acad. Sci. USA. 86:9762, 1989; Hayes, G. et al., Mol. Endocrinol. 6:920,1992) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 1.4 mMAscorbic Acid, 0.001% BSA, 150 mM NaCl) was used. Compounds of theinvention were incubated with 0.16 nM [³H]Spiperone for 120 min. at 25°C. Non-specific binding was estimated in the presence of 10 μMHaloperidol. Receptor proteins were filtered and washed, the filterswere then counted to determine [³H]Spiperone specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Biochemical assay results are presented as the percent inhibition ofspecific binding in Table 5.

TABLE 5 Inhibition of ligand binding to aminergic G protein-coupledreceptors by compounds of the invention: Dopamine Adrenergic (1 μM) (1μM) Comp. No. α_(1D) α_(2A) α_(2B) D2L 1 90 90 107 23 2 100 96 111 97 389 91 112 27 4 76 85 93 2 5 88 97 100 34 6 92 93 106 30 7 69 84 101 15 891 95 103 42 9 80 88 90 20 10 89 96 101 35 11 7 1 3 −11 12 68 101 103 4513 76 94 105 38 14 75 90 100 38 15 72 93 104 45 16 85 105 99 37 17 95105 99 34 18 58 92 98 3 19 54 69 90 12 20 91 68 88 13 21 17 −7 6 6 22 1−14 −7 0 23 17 42 25 4 24 85 100 99 41 25 96 100 104 43 26 94 99 104 6527 95 98 100 58 28 94 96 103 67 29 71 101 101 67 30 89 99 100 53 31 6 3123 4 32 4 39 22 −1 33 99 97 103 35 34 100 94 110 90 35 96 93 112 50 3695 96 101 34 37 14 68 70 9 38 38 77 83 21 39 99 98 105 66 40 64 96 10146 41 75 95 104 34 42 73 87 107 8 43 70 78 107 4 44 10 1 12 −8 45 1 −9 9−6 46 88 100 107 79 47 97 97 105 45 48 95 98 103 31 49 71 96 106 32 5084 94 102 34 51 85 98 103 30 52 91 97 103 20 53 13 1 3 2 54 −1 5 1 6 558 12 7 6 56 83 95 91 62 57 −7 −1 87 10 58 88 95 10 47 59 73 89 9 20 60−1 7 53 −9 61 −5 23 103 1 62 12 11 98 7 63 77 96 73 61 67 90 102 99 5068 93 99 100 40 69 −5 8 −4 −2 72 17 −6 7 −18 73 1 28 21 −14 74 17 19 27−2 75 7 7 21 2 76 37 7 31 0 77 81 85 113 16 78 102 83 111 58 79 −6 17 20−7 82 96 96 91 90 83 93 99 113 61 152 47 93 88 3 154 33 155 38 157 24158 98 99 109 65 160 17 174 89 101 105 34 176 23 177 25 179 23 180 98 99103 62 182 19 224 19 8 −6 −2 225 34 0 13 3 226 83 93 102 37 227 73 70 985 228 98 102 110 73 229 97 100 103 68 230 97 102 99 48 232 29 90 39 8233 96 97 100 73 234 97 98 100 71 235 95 95 98 42 236 94 89 103 34 23770 98 93 50 238 30 98 103 7 239 28 93 107 9 240 57 241 37 242 69 243 32244 43 245 16 246 14 247 8 248 81 249 35 250 15 251 35 252 19 253 55 28175 92 99 40 282 67 95 102 1 283 12 284 11 285 89 91 75 21

Example B5 Determination of the Ability of Compounds of the Invention toBind a Serotonin Receptor Serotonin (5-Hydroxytryptamine) 5-HT_(1A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(1A) receptor expressed in Chinese hamster ovary (CHO—K1) cells(Martin G R and Humphrey P P A. Neuropharmacol. 33:261, 1994; May J A,et al. J Pharmacol Exp Ther. 306(1): 301, 2003) in a modified Tris-HClbuffer (50 mM Tris-HCl, pH 7.4, 0.1% Ascorbic Acid, 0.5 mM EDTA, 10 mMMgSO₄) is used. Compounds of invention are incubated with 1.5 nM[³H]8-OH-DPAT for 60 min. at 25° C. Non-specific binding is estimated inthe presence of 10 μM Metergoline. Receptor proteins are filtered andwashed, the filters are then counted to determine [³H]8-OH-DPATspecifically bound. Compounds are screened at 1 μM or lower, using 1%DMSO as vehicle. Compounds of the invention are tested in thisbiochemical assay and percent inhibition of specific binding isdetermined.

Serotonin (5-Hydroxytryptamine) 5-HT_(1B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, serotonin (5-Hydroxytryptamine) 5-HT_(1B) receptor fromWistar Rat cerebral cortex (Hoyer et al. Eur J. Pharmaco. 118: 1, 1985;Pazos et al. Eur J. Pharmacol. 106: 531, 1985) in a modified Tris-HClbuffer (50 mM Tris-HCl, pH 7.4, 154 mM NaCl, 10 μM Pargyline, 30 μMIsoprenaline) is used. Compounds of invention are incubated with 10 pM[¹²⁵I]Cyanopindolol for 90 min. at 37° C. Non-specific binding isestimated in the presence of 10 μM Serotonin (5-HT). Receptor proteinsare filtered and washed, the filters are then counted to determine[¹²⁵I]Cyanopindolol specifically bound. Compounds are screened at 1 μMor lower, using 1% DMSO as vehicle. Compounds of the invention aretested in this biochemical assay and percent inhibition of specificbinding is determined.

Serotonin (5-Hydroxytryptamine) 5-HT_(2A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(2A) receptor expressed in Chinese hamster ovary (CHO—K1) cells(Bonhaus, D. W. et al. Br. J. Pharmacol. 115:622, 1995; Saucier, C. andAlbert, P. R., J. Neurochem. 68:1998, 1997) in a 50 mM Tris-HCl buffer,pH 7.4, was used. Compounds of the invention were incubated with 0.5 nM[³H]Ketanserin for 60 min. at 25° C. Non-specific binding was estimatedin the presence of 1 μM Mianserin. Receptor proteins were filtered andwashed, the filters were then counted to determine [³H]Ketanserinspecifically bound. Compounds were screened at 1 μM or lower, using 1%DMSO as vehicle. Biochemical assay results are presented as the percentinhibition of specific binding in Table 6.

Serotonin (5-Hydroxytryptamine) 5-HT_(2B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(2B) receptor expressed in Chinese hamster ovary (CHO—K1) cells(Bonhaus, D. W. et al., Br. J. Pharmacol. 115:622, 1995) in a modifiedTris-HCl buffer (50 mM Tris-HCl, pH 7.4, 4 mM CaCl₂, 0.1% Ascorbic Acid)is used. Compounds of invention are incubated with 1.2 nM [³H]Lysergicacid diethylamide (LSD) for 60 min. at 37° C. Non-specific binding isestimated in the presence of 10 μM Serotonin (5-HT). Receptor proteinsare filtered and washed, the filters are then counted to determine[³H]LSD specifically bound. Compounds are screened at 1 μM or lower,using 1% DMSO as vehicle. Compounds of the invention are tested in thisbiochemical assay and percent inhibition of specific binding isdetermined.

Serotonin (5-Hydroxytryptamine) 5-HT_(2C)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(2C) receptor expressed in Chinese hamster ovary (CHO—K1) cells(Wolf, W. A. and Schutz, J. S., J. Neurochem. 69:1449, 1997) in amodified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 0.1% Ascorbic Acid, 10μM Pargyline) was used. Compounds of the invention were incubated with 1nM [³H]Mesulergine for 60 min. at 25° C. Non-specific binding wasestimated in the presence of 1 μM Mianserin. Receptor proteins werefiltered and washed, the filters were then counted to determine[³H]Mesulergine specifically bound. Compounds were screened at 1 μM orlower, using 1% DMSO as vehicle. Biochemical assay results are presentedas the percent inhibition of specific binding in Table 6.

Serotonin (5-Hydroxytryptamine) 5-HT₃

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT₃receptor expressed in human embryonic kidney (HEK-293) cells (Miller Ket al. Synapase. 11:58, 1992; Boess F G et al. Neuropharmacology.36:637, 1997) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 1mM EDTA, 5 mM MgCl₂) is used. Compounds of invention are incubated with0.69 nM [³H]GR-65630 for 60 min. at 25° C. Non-specific binding isestimated in the presence of 10 μM MDL-72222. Receptor proteins arefiltered and washed, the filters are then counted to determine[³H]GR-65630 specifically bound. Compounds are screened at 1 μM orlower, using 1% DMSO as vehicle. Compounds of the invention are testedin this biochemical assay and percent inhibition of specific binding isdetermined.

Serotonin (5-Hydroxytryptamine) 5-HT₄

To evaluate in radioligand binding assays the activity of compounds ofthe invention, serotonin (5-Hydroxytryptamine) 5-HT₄ receptor fromDuncan Hartley derived Guinea pig striatum (Grossman C J et al. Br J.Pharmacol. 109:618, 1993) in a 50 mM Tris-HCl, pH 7.4, is used.Compounds of invention are incubated with 0.7 nM [³H]GR-113808 for 30min. at 25° C. Non-specific binding is estimated in the presence of 30μM Serotonin (5-HT). Receptor proteins are filtered and washed, thefilters are then counted to determine [³H]GR-113808 specifically bound.Compounds are screened at 1 μM or lower, using 1% DMSO as vehicle.Compounds of the invention are tested in this biochemical assay andpercent inhibition of specific binding is determined.

Serotonin (5-Hydroxytryptamine) 5-HT_(5A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(5A) receptor expressed in Chinese hamster ovary (CHO—K1) cells(Rees, S. et al., FEBS Lett. 355:242, 1994) in a modified Tris-HClbuffer (50 mM Tris-HCl, pH 7.4, 10 mM MgCl₂, 0.5 mM EDTA) is used.Compounds of the invention are incubated with 1.7 nM [³H]Lysergic aciddiethylamide (LSD) for 60 min. at 37° C. Non-specific binding isestimated in the presence of 100 μM Serotonin (5-HT). Receptor proteinsare filtered and washed, the filters are then counted to determine[³H]LSD specifically bound. Compounds are screened at 1 μM or lower,using 1% DMSO as vehicle. Compounds of the invention are tested in thisbiochemical assay and percent inhibition of specific binding isdetermined.

Serotonin (5-Hydroxytryptamine) 5-HT₆

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT6receptor expressed in human HeLa cells (Monsma, F. J. Jr. et al., Mol.Pharmacol. 43:320, 1993) in a modified Tris-HCl buffer (50 mM Tris-HCl,pH 7.4, 150 mM NaCl, 2 mM Ascorbic Acid, 0.001% BSA) was used. Compoundsof the invention were incubated with 1.5 nM [3H]Lysergic aciddiethylamide (LSD) for 120 min. at 37° C. Non-specific binding wasestimated in the presence of 5 μM Serotonin (5-HT). Receptor proteinswere filtered and washed, the filters were then counted to determine[3H]LSD specifically bound. Compounds were screened at 1 μM or lower,using 1% DMSO as vehicle. Biochemical assay results are presented as thepercent inhibition of specific binding in Table 6.

Serotonin (5-Hydroxytryptamine) 5-HT₇

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT₇receptor expressed in Chinese hamster ovary (CHO) cells (Roth, B. L. etal., J. Pharmacol. Exp. Ther. 268:1403, 1994; Shen, Y. et al., J. Biol.Chem. 268:18200, 1993) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH7.4, 10 mM MgCl₂, 0.5 mM EDTA) is used. Compounds of invention areincubated with 5.5 nM [³H]Lysergic acid diethylamide (LSD) for 2 hoursat 25° C. Non-specific binding is estimated in the presence of 10 μMSerotonin (5-HT). Receptor proteins are filtered and washed, the filtersare then counted to determine [³H]LSD specifically bound. Compounds arescreened at 1 μM or lower, using 1% DMSO as vehicle.

TABLE 6 Inhibition of ligand binding to aminergic G protein-coupledreceptors by compounds of the invention: Comp Serotonin (1 μM) No.5-HT_(2A) 5-HT_(2C) 5-HT₆ 1 98 79 86 2 99 88 103 3 95 94 92 4 93 89 83 596 90 93 6 96 92 82 7 80 64 36 8 97 95 100 9 96 93 81 10 94 92 97 11 534 4 12 100 92 83 13 97 89 100 14 101 95 93 15 101 100 82 16 101 92 7817 102 93 80 18 88 64 60 19 80 52 42 20 95 77 46 21 8 29 30 22 −2 −4 −1223 67 37 17 24 98 95 99 25 97 94 93 26 100 93 87 27 99 91 92 28 100 9495 29 100 101 103 30 100 98 86 31 43 56 2 32 60 48 4 33 100 86 98 34 9897 103 35 99 91 102 36 97 83 99 37 91 85 12 38 96 98 41 39 98 97 103 4097 97 101 41 99 99 101 42 95 101 73 43 93 91 48 44 17 41 1 45 22 16 2 46100 98 98 47 99 98 77 48 97 98 73 49 97 98 88 50 98 95 88 51 97 98 94 5297 96 84 53 41 32 −1 54 1 −2 −10 55 −2 32 4 56 97 95 104 57 10 65 −1 58100 16 99 59 93 −3 97 60 −7 −5 3 61 43 89 5 62 12 101 −4 63 91 5 101 67100 93 86 68 99 95 87 69 52 −1 −4 72 23 53 39 73 18 11 0 74 27 1 −4 7534 13 −2 76 52 78 39 77 90 72 33 78 100 98 91 79 −8 −18 −7 82 98 98 10483 99 100 103 152 100 94 73 154 100 99 92 155 99 98 101 157 98 101 78158 101 99 93 160 94 103 99 174 102 101 100 176 99 99 74 177 98 99 96179 98 100 77 180 101 100 95 182 101 102 96 224 −7 11 −4 225 38 44 16226 92 82 36 227 85 66 30 228 99 97 104 229 100 98 102 230 97 96 100 23270 93 20 233 102 100 103 234 101 98 103 235 102 98 97 236 101 100 102237 99 100 103 238 103 100 86 239 102 97 59 240 98 97 102 241 100 97 100242 99 94 102 243 98 102 99 244 100 101 103 245 99 99 97 246 98 99 94247 98 99 74 248 99 101 103 249 100 98 101 250 100 99 99 251 101 99 99252 96 87 98 253 102 101 103 281 100 98 97 282 98 103 71 283 90 100 40284 94 100 42 285 100 99 94

Example B6 Determination of Serotonin (5-Hydroxytryptamine) 5-HT_(2A)Agonist/Antagonist Activity of Compounds of the Invention

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant serotonin 5-HT_(2A)receptor expressed in human embryonic kidney (HEK-293) cells (Jerman JC, Brough S J, Gager T, Wood M, Coldwell M C, Smart D and Middlemiss DN. Eur J Pharmacol, 414: 23-30, 2001) is used. Cells are suspended inDMEM buffer, and distributed in microplates. A cytoplasmic calciumfluorescent indicator which varies proportionally to the free cytosolicCa²⁺ ion concentration is mixed with probenecid in HBSS buffercomplemented with 20 mM HEPES (pH 7.4), added into each well andequilibrated with the cells for 30 min. at 37° C. followed by 30 min. at22° C.

To measure agonist effects, compounds of the invention, referenceagonist or HBSS buffer (basal control) is added to the cells and changesin fluorescence intensity are measured using a microplate reader. Forstimulated control measurements, 5-HT at 100 nM is added in separateassay wells.

The results are expressed as a percent of the control response to 100 nM5-HT. The standard reference agonist is 5-HT, which is tested in eachexperiment at several concentrations to generate aconcentration-response curve from which its EC₅₀ value is calculated.

To measure antagonist effects, the addition of the compounds of theinvention, reference antagonist or HBSS buffer is followed by theaddition of 3 nM 5-HT or HBSS buffer (basal control) prior thefluorescence measurements. The results are expressed as a percentinhibition of the control response to 3 nM 5-HT. The standard referenceantagonist is ketanserin, which is tested in each experiment at severalconcentrations to generate a concentration-response curve from which itsIC₅₀ value is calculated. Compounds are screened at 3 μM or lower, usingDMSO as vehicle.

Example B7 Determination of Serotonin (5-Hydroxytryptamine) 5-HT6Agonist/Antagonist Activity of Compounds of the Invention

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant 5-HT₆ receptor istransfected in CHO cells (Kohen, R., Metcalf, M. A., Khan, N., Druck,T., Huebner, K., Lachowicz, J. E., Meltzer, H. Y., Sibley, D. R., Roth,B. L. And Hamblin, M. W. Cloning, characterization and chromosomallocalization of a human 5-HT6 serotonin receptor, J. Neurochem., 66: 47,1996) and the activity of compounds of the invention is determined bymeasuring their effects on cAMP production using the Homogeneous TimeResolved Fluorescence (HTRF) detection method. Cells are suspended inHBSS buffer complemented with HEPES 20 mM (pH 7.4) and 500 μM IBMX, andthen distributed in microplates and incubated for 45 min. at 37° C. inthe absence (control) or presence of compounds of the invention or thereference agonist or antagonist.

For agonist determinations, stimulated control measurement, separateassay wells contain 10 μM 5-HT. Following incubation, the cells arelysed and the fluorescence acceptor (D2-labeled cAMP) and fluorescencedonor (anti-cAMP antibody labeled with europium cryptate) are added.After 60 min. at RT, the fluorescence transfer is measured at lex=337 nmand lem=620 and 665 nm using a microplate reader. The cAMP concentrationis determined by dividing the signal measured at 665 nm by that measuredat 620 nm (ratio).

The results are expressed as a percent of the control response to 10 μM5-HT. The standard reference agonist is 5-HT, which is tested in eachexperiment at several concentrations to generate aconcentration-response curve from which its EC₅₀ value is calculated.

For antagonist determinations, the reference agonist 5-HT is added at afinal concentration of 100 nM. For basal control measurements, separateassay wells do not contain 5-HT. Following 45 min. incubation at 37° C.,the cells are lysed and the fluorescence acceptor (D2-labeled cAMP) andfluorescence donor (anti-cAMP antibody labeled with europium cryptate)are added.

After 60 min. at RT, the fluorescence transfer is measured as mentionedabove. The results are expressed as a percent inhibition of the controlresponse to 100 nM 5-HT. The standard reference antagonist ismethiothepin.

Example B8 Determination of Dopamine D2L Antagonist Activity ofCompounds

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant dopamine D_(2L)receptor stably expressed in Chinese hamster ovary (CHO) cells (SenoglesS E et al. J Biol. Chem. 265(8): 4507, 1990) is used. Compounds ofinvention are pre-incubated with the membranes (0.1 mg/mL) and 10 mM GDPin modified HEPES buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl₂,1 mM DTT, 1 mM EDTA) for 20 min. and Scintillation Proximity Assay (SPA)beads are added for another 60 min. at 30° C. The reaction is initiatedby 0.3 nM [³⁵S]GTPγS for an additional 15 min. incubation period.Increase of [³⁵S]GTPγS binding by 50 percent or more (350%) relative tothe 1 mM dopamine response indicates possible dopamine D_(2L) receptoragonist activity. Inhibition of a 10 μM dopamine-induced increase of[³⁵S]GTPγS binding response by 50 percent or more (350%) indicatesreceptor antagonist activity. Compounds are screened at 3 μM or lower,using 0.4% DMSO as vehicle. Assay results are presented as the percentresponse of specific binding.

Example B9 Determination of Dopamine D2S Antagonist Activity ofCompounds of the Invention

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant dopamine D_(2S)receptor stably expressed in Chinese hamster ovary (CHO) cells(Gilliland S L and Alper R H. Naunyn-Schmiedeberg's Archives ofPharmacology. 361: 498, 2000) is used. Compounds of invention arepre-incubated with the membranes (0.05 mg/mL) and 3 μM GDP in modifiedHEPES buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl₂, 1 mM DTT, 1mM EDTA) for 20 min. and Scintillation Proximity Assay (SPA) beads arethen added for another 60 min. at 30° C. The reaction is initiated by0.3 nM [³⁵S]GTPγS for an additional 30 min. incubation period. Increaseof [³⁵S]GTPγS binding by 50 percent or more (350%) relative to the 100μM dopamine response indicates possible dopamine D_(2S) receptor agonistactivity. Inhibition of a 3 μM dopamine-induced increase of [³⁵S]GTPγSbinding response by 50 percent or more (350%) indicates receptorantagonist activity. Compounds are screened at 3 μM or lower, using 0.4%DMSO as vehicle. Assay results are presented as the percent response ofspecific.

Example B10 Determination for Agonist or Antagonist Activity ofCompounds of the Invention in a Histamine H1 Functional Assay

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant Histamine H₁ receptorexpressed in human embryonic kidney (HEK-293) cells (Miller, T. R.,Witte, D. G., Ireland, L. M., Kang, C. H., Roch, J. M., Masters, J. N.,Esbenshade, T. A And Hancock, A. A. J. Biomol. Screen., 4: 249-258,1999) is used. Cells are suspended in DMEM buffer, and then distributedin microplates. A cytoplasmic calcium fluorescent indicator which variesproportionally to the free cytosolic Ca²⁺ ion concentration is mixedwith probenecid in HBSS buffer complemented with 20 mM HEPES (pH 7.4)and is then added into each well and equilibrated with the cells for 30min. at 37° C. and then for another 30 min. at 22° C. To measure agonisteffects, compounds of the invention, reference agonist or HBSS buffer(basal control) are added to the cells and changes in fluorescenceintensity are measured using a microplate reader. For stimulated controlmeasurements, histamine at 10 μM is added in separate assay wells.

The results are expressed as a percent of the control response to 10 μMhistamine. The standard reference agonist is histamine, which is testedin each experiment at several concentrations to generate aconcentration-response curve from which its EC₅₀ value is calculated.

To measure antagonist effects, the addition of the compounds of theinvention, reference antagonist or HBSS buffer is followed by theaddition of 300 nM histamine or HBSS buffer (basal control) prior thefluorescence measurements. The results are expressed as percentinhibition of the control response to 300 nM histamine. The standardreference antagonist is ketanserin, which is tested in each experimentat several concentrations to generate a concentration-response curvefrom which its IC₅₀ value is calculated. Compounds are screened at 3 μMor lower, using DMSO as vehicle.

Example B11 Increase of Neurite Outgrowth of Neurons that were Culturedwith Compounds of the Invention Neurite Outgrowth in Cortical Neurons

Compounds are tested to determine their ability to stimulate neuriteoutgrowth of cortical neurons. Standard methods are used to isolatecortical neurons. For the isolation of primary rat cortical neurons, thefetal brain from a pregnant rat at 17 days of gestation is prepared inLeibovitz's medium (L15; Gibco). The cortex is dissected out, and themeninges are removed. Trypsin (Gibco) is used to dissociate cortical Cwith DNAse I. The cells are triturated for 30 min. with a pipette inDulbecco's Modified Eagle Media (“DMEM”; Gibco) with 10% Fetal BovineSerum (“FBS”) (Gibco) and centrifuged at 350×g for 10 min. at RT. Thecells are suspended in Neurobasal medium supplemented with 2% B27(Gibco) and 0.5 mM L-glutamine (Gibco). The cells are maintained at30,000 cells per well of poly-L-lysine coated plates at 37° C. in 5%CO₂-95% air atmosphere. After adhesion, a vehicle control or compoundsof the invention are added at different concentrations to the medium.BDNF (50 ng/mL) is used as a positive control for neurite growth. Aftertreatment, cultures are washed in phosphate-buffered saline (“PBS”;Gibco) and fixed in glutaraldehyde 2.5% in PBS. Cells are fixed after 3days growth. Several pictures (˜80) of cells with neurites are taken percondition with a camera. The length measurements are made by analysis ofthe pictures using software from Image-Pro Plus (France). The resultsare expressed as mean (s.e.m.). Statistical analysis of the data isperformed using one way analysis of variance (ANOVA).

Neurite Outgrowth in Rat Mixed Cortical Cultures

Cortical mixed cultures are prepared from E18 Wistar rat embryos. Thecortices are dissected out and the tissue was cut to small pieces. Thecells are separated by 15-min. incubation with DNase and papain. Thecells are collected by centrifugation (1500 rpm, 5 min.). The tissue istriturated with a pipette and the cells are plated using the micro-isletprotocol (20 000 cells in 25 μl medium) on poly-L-lysine coated 48wells, in MEM supplemented with 2 mM glutamine, 0.1 μg/mL gentamicin,10% heat-inactivated fetal bovine serum (FBS-HI) and 10%heat-inactivated horse serum (HS-HI). After the cells has attached tothe well, 250 μl medium is added to the wells. Four hours after platingthe medium is changed to fresh medium (MEM with supplements and 5%HS-HI) containing test compound at 0.5, 5 and 50 nM concentrations. Aspositive controls BDNF (50, 100 and/or 150 ng/mL), and/or NGF (50 ng/mLand/or 100 ng/mL) are used. After 2 days in vitro, the cell'sconditioned media are collected from plates before fixing the cells. Themedia samples are centrifuged 13 000 rpm 3 min. to get rid of celldebris. The samples are stored at −20 C for later analysis. Cells areformaldehyde-fixed and processed for immunocytochemistry. BDNF levels inthe conditioned media are determined with a BDNF ELISA using themanufacturers (Promega, BDNF Emax® ImmunoAssay System, catalog number:G7610) instructions.

The cultures are fixed with 4% formaldehyde in 0.01 M PBS for 30 min.and washed once with PBS. The fixed cells are first permeabilized andnon-specific binding is blocked by a 30-min. incubation with blockingbuffer containing 1% bovine serum albumin and 0.3% Triton X-100 in PBS.Rabbit anti-MAP-2 (dilution 1:1000, AB5622, Chemicon, in blockingbuffer) is used as a primary antibody. The cells are incubated with theprimary antibody for 48 h at +4° C., washed with PBS and incubated withsecondary antibody goat anti-rabbit IgG conjugated to Alexa Fluor568(1:200, A11036, Molecular Probes) for 2 h at RT. The immunopositivecells are visualized by a fluorescence microscope equipped withappropriate filter set, and documented by a high resolution imagecapturing. The number of cells per field (4 field per well) are counted,and the neurite outgrowth is quantified using Image Pro Plus software.

The number of wells per compound concentration used is 6 (n=6). All dataare presented as mean±standard deviation (SD) or standard error of mean(SEM), and differences are considered to be statistically significant atthe p<0.05 level. Statistical analysis is performed using StatsDirectstatistical software. Differences between group means are analyzed byusing 1-way-ANOVA followed by Dunnet's test (comparison to the vehicletreated group).

Example B12 Use of an In Vivo Model to Evaluate the Ability of Compoundsto Enhance Cognition, Learning and Memory in Scopolamine Treated Rats

The two-trial object recognition paradigm developed by Ennaceur andDelacour in the rat is used as a model of episodic/short term memory.Ennaceur, A., and Delacour, J. (1988), Behav. Brain Res. 31:47-59. Theparadigm is based on spontaneous exploratory activity of rodents anddoes not involve rule learning or reinforcement. The novel objectrecognition paradigm is sensitive to the effects of ageing andcholinergic dysfunction. See, e.g., Scali, C., et al., (1994), Neurosci.Letts. 170:117-120; and Bartolini, L., et al., (1996), Biochem. Behav.53:277-283.

Male Sprague-Dawley rats between six and seven weeks old, weighingbetween 220-300 grams are obtained from Centre d'Elevage (Rue Janvier,B.P. 55, Le Genest-Saint-Isle 53940, France). The animals are housed ingroups of 2 to 4 in polypropylene cages (with a floor area of 1032 cm²)under standard conditions: at RT (22±2° C.), under a 12 hour light/12hour dark cycle, with food and water provided ad libitum. Animals arepermitted to acclimate to environmental conditions for at least 5 daysbefore the experiment begins, and are numbered on their tails withindelible marker.

The experimental arena is a square wooden box (60 cm×60 cm×40 cm)painted dark blue, with 15 cm×15 cm black squares under a clearplexiglass floor. The arena and objects placed inside the arena arecleaned with water between each trial to eliminate any odor trails leftby rats. The arena is placed in a dark room illuminated only by halogenlamps directed towards the ceiling in order to produce a uniformly dimlight in the box of approximately 60 lux. The day before testing,animals are allowed to freely explore the experimental arena for threemin. in the presence of two objects (habituation). Animals to be testedare placed in the experimental room at least 30 min. before testing.

Novel object recognition test is comprised of two trials separated by aninterval of 120 min. or 24 h. When agents that disrupt memory such asthe cholinergic antagonist scopolamine are used an inter-trial intervalof 120 min. is preferred. Alternatively a 24 h inter-trial interval isused when studying effect of natural forgetting on novel objectrecognition task. During the first, or acquisition, trial (T₁), rats areplaced in the arena, where two identical objects have been previouslyplaced. The time required for each animal to complete 15 seconds ofobject exploration is determined, with a cut-off time of four min.Exploration is considered to be directing the nose at a distance lessthan 2 centimeters (“cm”) from the object and/or touching the object.During the second, or testing, trial (T₂), one of the objects presentedin the first trial is replaced with an unknown or novel object, whilethe second, familiar object was left in place. Rats are placed back inthe arena for three min., and exploration of both objects is determined.Locomotor activity of rats (number of times rats cross grid linesvisible under the clear plexiglass floor) is scored for during T₁ andT₂. At the conclusion of the experiments, the rats are sacrificed by anoverdose of pentobarbital given intraperitoneally.

The following parameters are measured as part of the novel objectrecognition task: (1) time required to achieve 15 seconds of objectexploration during T₁; (2) locomotor activity during T₁ (number ofcrossed lines); (3) time spent in active exploration of the familiarobject during T₂ (T_(Familiar)); (4) time spent in active exploration ofthe novel object during T₂ (T_(Novel)); and (5) locomotor activityduring T₂ (number of crossed lines). The difference between time spentin active exploration of the novel object during T₂ and time spent inactive exploration of the familiar object during T₂ (δT_(Novel)-T_(Familiar)) is evaluated. The % of animals in each groupwith T_(Novel)-T_(Familiar) greater than or equal to 5 seconds is alsoderived; described as % of good learners.

Animals not meeting a minimal level of object exploration are excludedfrom the study as having naturally low levels of spontaneousexploration. Only rats exploring the objects for at least five seconds(T_(Novel)+T_(Familiar)>5 seconds) are included in the study.

Animals are randomly assigned to groups of 14. Compounds of theinvention and controls are administered to animals the groups asfollows: Solutions of compounds are prepared freshly each day at aconcentration of 0.25 mg/mL using purified water or saline as vehicle.Donepezil, used as a positive control, and scopolamine are administeredsimultaneously in a single solution of saline (5 mL/kg) prepared freshlyeach day. Scopolamine is purchased from Sigma Chemical Co. (Catalog No.S-1875; St. Quentin Fallavier, France) is dissolved in saline to aconcentration of 0.06 mg/mL.

Donepezil or its vehicle and scopolamine are administeredintraperitoneally 40 min. before the acquisition trial (T₁). Compoundsor their vehicle are administered by gavage 25 min. before theacquisition trial (T₁), i.e., 5 min. after administration ofscopolamine. The volume of administration is 5 mL/kg body weight forcompounds administered intraperitoneally, and 10 mL/kg for compoundsadministered orally. Recognition scores and % of good learners forcompounds of the invention are determined.

Example B13 Use of an In Vivo Model to Determine the Ability ofCompounds to Treat, Prevent and/or Delay the Onset and/or theDevelopment of Schizophrenia in PCP Treated Animals

In vivo models of schizophrenia can be used to determine the ability ofthe compounds described herein to treat and/or prevent and/or delay theonset and/or the development of schizophrenia.

One exemplary model for testing the activity of one or more compoundsdescribed herein to treat and/or prevent and/or delay the onset and/ordevelopment of schizophrenia employs phencyclidine (PCP), which isadministered to the animal (e.g., non-primate (rat) or primate(monkey)), resulting in dysfunctions similar to those seen inschizophrenic humans. See Jentsch et al., 1997, Science 277:953-955 andPiercey et al., 1988, Life Sci. 43(4):375-385). Standard experimentalprotocols may be employed in this or in other animal models. Oneprotocol involves PCP-induced hyperactivity.

Male mice (various strains, e.g., C57Bl/6J) from appropriate vendor (forexample, Jackson Laboratories (Bar Harbor, Me.) are used. Mice arereceived at 6-weeks of age. Upon receipt, mice are assigned uniqueidentification numbers (tail marked) and are group housed with 4mice/cage in OPTI mouse ventilated cages. All animals remained housed ingroups of four during the remainder of the study. All mice areacclimated to the colony room for at least two weeks prior to testingand are subsequently tested at an average age of 8 weeks. During theperiod of acclimation, mice are examined on a regular basis, handled,and weighed to assure adequate health and suitability. Animals aremaintained on a 12/12 light/dark cycle. The room temperature ismaintained between 20 and 23° C. with a relative humidity maintainedbetween 30% and 70%. Food and water are provided ad libitum for theduration of the study. In each test, animals are randomly assignedacross treatment groups.

The open filed (OF) test assesses locomotor behavior, i.e. to measuremouse locomotor activity at baseline and in response to pharmacologicalagents. The open field chambers are Plexiglas square chambers(27.3×27.3×20.3 cm; Med Associates Inc., St Albans, Vt.) surrounded byinfrared photobeams (16×16×16) to measure horizontal and verticalactivity. The analysis is configured to divide the open field into acenter and periphery zone such that the infrared photobeams allowmeasurement of activity in the center and periphery of the field.Distance traveled is measured from horizontal beam breaks as the mousemoved whereas rearing activity is measured from vertical beam breaks.

Mice (10 to 12 animals per treatment group) are brought to the activityexperimental room for at least 1 h acclimation to the experimental roomconditions prior to testing. Eight animals are tested in each run. Miceare administered vehicle (e.g., 10% DMSO or 5% PEG200 and 1% Tween 80),compound of the invention, clozapine (positive control, 1 mg/kg ip) andplaced in the OF chambers for 30 min. following which they are injectedwith either water or PCP and placed back in the OF chambers for a60-min. session. At the end of each OF test session the OF chambers arethoroughly cleaned.

PCP Hyperactivity Mouse Model of Schizophrenia

The test compound at the desired dose is dissolved in appropriatevehicle, e.g., 5% PEG200, 1% Tween 80 and administered orally 30 min.prior to PCP injection. Clozapine (1 mg/kg) is dissolved in 10% DMSO andadministered i.p. 30 min. prior to PCP injection. PCP (5 mg/kg) isdissolved in sterile injectable saline solution and administered i.p.Data are analyzed by analysis of variance (ANOVA) followed by post-hoccomparisons with Fisher Tests when appropriate. Baseline activity ismeasured during the first 30 min. of the test prior to PCP injection.PCP-induced activity is measured during the 60 min. following PCPinjection. Statistical outliers that fell above or below 2 standarddeviations from the mean are removed from the final analyses. An effectis considered significant if p<0.05. Total distances traveled and totalrearing following PCP administration are compared between groups treatedwith compounds and groups treated with vehicle and positive controlclozapine.

Example B14 Use of an In Vivo Model to Determine the Ability ofCompounds to Treat, Prevent and/or Delay the Onset and/or theDevelopment of Schizophrenia in Amphetamine Treated Animals

Male mice (various strains e.g., C57Bl/6J) from appropriate supplier(for example Jackson Laboratories, Bar Harbor, Me.) are used. Micetypically are received at 6-weeks of age. Mice are acclimated to thecolony room for at least two weeks prior to testing. During the periodof acclimation, mice are examined on a regular basis, handled, andweighed to assure adequate health and suitability and maintained on a12/12 light/dark cycle. The room temperature is maintained between 20and 23° C. with a relative humidity maintained between 30% and 70%. Foodand water are provided ad libitum for the duration of the study. In eachtest, animals are randomly assigned between treatment groups.

The open field test (OF) is used to assess motor activity. The openfield chambers are plexiglas square chambers (e.g., 27.3×27.3×20.3 cm;Med Associates Inc., St Albans, Vt.) surrounded by infrared photobeamsources (16×16×16). The enclosure is configured to split the open fieldinto a center and periphery zone and the photocell beams are set tomeasure activity in the center and in the periphery of the OF chambers.Horizontal activity (distance traveled) and vertical activity (rearing)are measured from consecutive beam breaks.

On the day of testing, animals are brought to the experimental room forat least 1 h acclimation prior to start of treatment. Animals areadministered with vehicle, haloperidol (positive control, 0.1 mg/kg ip)or test compound and placed in the OF. The time of administration ofclient compound to each animal is recorded. Baseline activity isrecorded for 30 min. following which mice receive amphetamine (4 mg/kg)or water and are placed back in the OF chambers for a 60-min. session.At the end of each open field test session the OF chambers arethoroughly cleaned. Typically ten to twelve mice are tested in eachgroup. Test compound doses typically range from 0.01 mg/kg to 60 mg/kg.Data are analyzed by analysis of variance (ANOVA) followed by post-hoccomparisons with Fisher Tests when appropriate. Baseline activity ismeasured during the first 30 min of the test prior to amphetamineinjection. Amphetamine-induced activity is measured during the 60 minfollowing amphetamine injection. Statistical outliers that fall above orbelow 2 standard deviations from the mean are removed from the finalanalyses. An effect is considered significant if p<0.05. Total distancetraveled and total rearing following amphetamine administration arecompared between groups treated with compound and groups treated withvehicle and positive control haloperidol.

Example B15 Use of the In Vivo Conditioned Avoidance Response (CAR)Model to Determine the Ability of Compounds to Treat, Prevent and/orDelay the Onset and/or the Development of Schizophrenia

All currently approved antipsychotic agents (typical and atypical) areknown to have the ability to selectively suppress conditioned avoidanceresponse (CAR) behavior in the rat. This evidence makes CAR one of theprimary tests to assess antipsychotic activity of novel compounds. Rats(various strains, 2 months of age) are trained and tested in acomputer-assisted, two-way active avoidance apparatus (shuttle box).This box consists of two compartments of equal size divided by astainless steel partition containing an opening of 7×7 cm. Eachcompartment is equipped with an electrified grid floor made of stainlesssteel rods spaced 1 cm apart. Rats trained to avoid the foot shock areplaced each day in the shuttle box for a 4 min. habituation periodfollowed by 30 trials spaced by inter-trial interval varying at randombetween 20 and 30 sec. Each trial consists of a 10-sec. stimulus light(conditioned stimulus, CS) followed by a 10-sec. foot shock(unconditioned stimulus, US) in presence of the light presented in thecompartment where the rat is located. If the animal leaves thecompartment prior to the delivery of the foot shock, the response isconsidered an avoidance response. If the rat does not change compartmentduring the 10-sec. light period and during the 10-sec. shock+lightperiod, an escape failure is recorded. This test requires animals to betrained 5 d/week. On each training day, rats are submitted to onetraining session of 30-trials. Treatment with test compound is initiatedonly when rats reach an avoidance performance of at least 80% on atleast two consecutive training sessions. The test compound isadministered orally at various doses and various pre-treatment times(depending upon specific pharmacokinetic properties).

Compounds with antipsychotic profile inhibit conditioned avoidanceresponses with or without increases in escape failures. Statisticalanalysis is performed using a Friedman two-way ANOVA by ranks followedby the Wilcoxon matched-pairs signed-ranks test to test each dose of thetest compound administered versus vehicle control treated rats.

Example B16 An Animal Model of the Negative Symptoms of Schizophrenia:Subchronic PCP-Induced Social Interaction Deficits

Phencyclidine (PCP) administered to humans as well to experimentalanimals induces full-spectrum of schizophrenia symptoms, includingnegative symptoms and cognitive deficits. A major symptom ofschizophrenia is considered to be social isolation/withdrawal as part ofthe cluster of negative symptoms. Subchronic treatment with PCP in ratsleads to the development of clear signs of social withdrawal as measuredby deficits in the interaction time with a cage intruder rat. MaleSprague Dawley rats (about 150 g, obtained from different vendors, forexample Harlan, Ind.) are used in this study. Upon receipt, rats aregroup housed in OPTI rat ventilated cages. Rats are housed in groups of2-3 per cage for the remainder of the study. During the period ofacclimation, rats are examined on a regular basis, handled, and weighedto assure adequate health and suitability. Rats are maintained on a12/12 light/dark cycle with the light on at 7:00 a.m. The roomtemperature is maintained between 20-23° C. with a relative humiditymaintained between 30-70%. Food and water are provided ad libitum forthe duration of the study. Animals are randomly assigned acrosstreatment groups and balanced by age.

For five days prior to test, rats are injected twice daily with eitherPCP (2 mg/kg; s.c) or saline (s.c). On day 6 and following a 30 minpretreatment with vehicle, clozapine (2.5 mg/kg ip dissolved in 5%PEG:5% Tween 80) as positive control and test compound at desired dosedissolved in appropriate vehicle, a pair of rats, unfamiliar to eachother, receiving the same treatment are placed in a white plexiglas openfield arena (24″×17″×8″) and allowed to interact with each other for 6min. Social interactions (‘SI’) include: sniffing the other rat;grooming the other rat; climbing over or under or around the other rat;following the other rat; or exploring the ano-genital area of the otherrat. Passive contact and aggressive contact are not considered a measureof social interaction. The time the rats spent interacting with eachother during the 6 min. test is recorded by a trained observer. Thesocial interaction chambers are thoroughly cleaned between the differentrats. Data are analyzed by analysis of variance (ANOVA) followed bypost-hoc analysis (e.g., Fischer, Dunnett) when appropriate. An effectis considered significant if p<0.05.

Example B17 An Animal Model of Extrapyramidal Syndrome (EPS):Measurement of Catalepsy in the Mouse Bar Test

Antipsychotic drugs are known to induce extrapyramidal syndrome (EPS) inanimals and in humans. An animal model considered to be predictive ofEPS is the mouse bar test, which measures cataleptic responses topharmacological agents. Male mice (various strains) from appropriatevendor (for example, Jackson Laboratories (Bar Harbor, Me.) are used.Mice are received at 6-weeks of age. Upon receipt, mice are assignedunique identification numbers (tail marked) and are group housed with 4mice per cage in OPTI mouse ventilated cages. All animals remain housedin groups of four during the remainder of the study. All mice areacclimated to the colony room for at least two weeks prior to testingand are subsequently tested at an average age of 8 weeks. During theperiod of acclimation, mice are examined on a regular basis, handled,and weighed to assure adequate health and suitability. Animals aremaintained on a 12/12 light/dark cycle. The room temperature ismaintained between 20-23° C. with a relative humidity maintained between30-70%. Food and water are provided ad libitum for the duration of thestudy. In each test, animals are randomly assigned across treatmentgroups.

In the mouse bar test, the front paws of a mouse are placed on ahorizontal bar raised 2″ above a Plexiglas platform and time is recordedfor up to 30 sec. per trial. The test ends when the animal's front pawsreturn to the platform or after 30 sec. The test is repeated 3 times andthe average of 3 trials is recorded as index of catalepsy. In thesestudies the typical antipsychotic agent haloperidol (2 mg/kg ipdissolved in 10% DMSO) is used as positive control and induces rigidityand catalepsy as measured by time spent holding on the bar. 30 min.prior to the trial, test compound at desired dose and dissolved inappropriate vehicle is administered PO, vehicle and positive controlhaloperidol (2 mg.kg ip) are administered to separate groups of mice.Catalepsy responses are measure 30 min., 1 h and 3 h followingtreatments. A trained observer is measuring time spent holding onto thebar during the 30 sec. trial. Data are analyzed by analysis of variance(ANOVA) followed by post-hoc analysis (e.g., Fischer, Dunnett) whenappropriate. An effect is considered significant if p<0.05.

Example B18 An Animal Model to Test the Anxiolytic Effects of CompoundsUsing the Elevated Plus Maze (EPM) Test

This study may be used to test the anxiolytic properties of compoundsdetailed herein using the elevated plus maze (EPM) test in C57Bl/6Jmice.

Male C57Bl/6J mice from Jackson Laboratories (Bar Harbor, Me.) are usedfor the open field study. Mice are received at 6-weeks of age. Uponreceipt, mice are assigned unique identification numbers (tail marked)and are group housed with 4 mice/cage in OPTI mouse ventilated cages.All animals remain housed in groups of four during the remainder of thestudy. All mice are acclimated to the colony room for approximately 2week prior to testing and are subsequently tested at an average age of 8weeks of age. During the period of acclimation, mice and rats areexamined on a regular basis, handled, and weighed to assure adequatehealth and suitability. Animals are maintained on a 12 h/12 h light/darkcycle. The room temperature is maintained between 20 and 23° C. with arelative humidity maintained between 30% and 70%. Chow and water areprovided ad libitum for the duration of the study. In each test, animalsare randomly assigned across treatment groups. All animals areeuthanized after the completion of the study.

Compounds may be dissolved in 5% PEG200/H₂O and administered orally at adose volume of 10 mL/kg 30 min prior to test; 2) Diazepam (2.5 mg/kg) isdissolved in 45% hydroxypropyl-β-cyclodextrin and administered orally ata dose volume of 10 mL/kg 30 min prior to test.

The elevated plus maze test assesses anxiety. The maze (Hamilton Kinder)consists of two closed arms (14.5 h×5 w×35 cm length) and two open arms(6 w×35 l cm) forming a cross, with a square center platform (6×6 cm).All visible surfaces are made of black acrylic. Each arm of the maze isplaced on a support column 56 cm above the floor. Antistatic black vinylcurtains (7′ tall) surround the EPM to make a 5′×5″ enclosure. Animalsare brought to acclimate to the experimental room at least 1 h beforethe test. Mice are placed in the center of the elevated plus maze facingthe closed arm for a 5-min run. All animals are tested once. The timespent, distance traveled and entries in each arm are automaticallyrecorded by a computer. The EPM is thoroughly cleaned after each mouse.

Data are analyzed using analysis of variance (ANOVA) followed byFisher's LSD post hoc analysis when appropriate. An effect is consideredsignificant if p<0.05.

All references throughout, such as publications, patents, patentapplications and published patent applications, are incorporated hereinby reference in their entireties.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is apparent to those skilled in the art that certainminor changes and modifications will be practiced. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention.

1. A compounds of the formula (I):

where: R¹ is H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy; each R^(2a), R^(2b), R^(3a) and R^(3b) isindependently H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy, or is taken together with the carbon to which itis attached and a geminal R² or R³ to form a cycloalkyl moiety or acarbonyl moiety; each R^(10a), R^(10b), R^(11a) and R^(11b) isindependently H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted amino, acylamino,aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl,sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy,or is taken together with the carbon to which it is attached and ageminal R¹⁰ or R¹¹ to form a cycloalkyl moiety or a carbonyl moiety;each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴; each R⁴ isindependently H, hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, thioalkyl, substituted or unsubstituted amino, acylamino,aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl,sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino oracyl; each m and q is independently 0 or 1; each R^(8a), R^(8b), R^(8c),R^(8d), R^(8e) and R^(8f) is independently H, hydroxyl, alkoxy, halo,C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, or is takentogether with a geminal R⁸ to form a moiety of the formula —OCH₂CH₂O—,is taken together with the carbon to which it is attached and a geminalR⁸ to form a cycloalkyl moiety or a carbonyl moiety, is taken togetherwith a geminal R⁸ to form a methylene or a substituted methylene, istaken together with a vicinal R⁸ and the carbon atoms to which they areattached to form a substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl or substituted orunsubstituted heterocyclyl moiety or is taken together with a vicinal R⁸to form a bond, provided when an R⁸ is taken together with a vicinal R⁸to form a bond, the geminal R⁸ is other than hydroxyl; Q is asubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano oralkynyl; or a salt or solvate thereof.
 2. The compound of claim 1,wherein X⁷, X⁸, X⁹ and X¹⁰ are CR⁴.
 3. The compound of claim 1, whereinat least one of X⁷, X⁸, X⁹ and X¹⁰ is N.
 4. The compound of claim 1,wherein each R⁴ is independently H, halo, unsubstituted C₁-C₄ alkyl,C₁-C₄ perhaloalkyl or a substituted or unsubstituted aryl.
 5. Thecompound of claim 1, wherein R¹ is H, substituted or unsubstituted C₁-C₈alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl.
 6. Thecompound of claim 1, wherein R¹ is methyl, ethyl, cyclopropyl,propylate, trifluoromethyl, isopropyl, tert-butyl, sec-butyl,2-methylbutyl, propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal,2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl,cyclopentyl, cyclohexyl, substituted phenyl, piperidin-4-yl,hydroxycyclopent-3-yl, hydroxycyclopent-2-yl, hydroxycycloprop-2-yl,1-hydroxy-1-methylcycloprop-2-yl, or1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl.
 7. The compound of claim 1,wherein: each R^(2a) and R^(2b) is independently H, unsubstituted C₁-C₈alkyl, halo or R^(2a) and R^(2b) are taken together to form a carbonylmoiety; and each R^(3a) and R^(3b) is independently H, unsubstitutedC₁-C₈ alkyl, halo or R^(3a) and R^(3b) are taken together to form acarbonyl moiety.
 8. The compound of claim 7, wherein each of R^(2a),R^(2b), R^(3a) and R^(3b) is H.
 9. The compound of claim 1, wherein eachR^(10a), R^(10b), R^(11a) and R^(11b) is independently H, bromo, methyl,hydroxyl or R^(10a) and R^(10b) are taken together with the carbon towhich they are attached to form a carbonyl or R^(11a) and R^(11b) aretaken together with the carbon to which they are attached to form acarbonyl.
 10. The compound of claim 1, wherein each R^(8a), R^(8b),R^(8c), R^(8d), R^(8e) and R^(8f) is independently H, hydroxyl,unsubstituted C₁-C₄ alkyl or is taken together with the carbon to whichit is attached and a geminal R₈ to form a cycloalkyl moiety.
 11. Thecompound of claim 1, wherein at least one of R^(8a), R^(8b), R^(8c),R^(8d), R^(8e) and R^(8f) is taken together with a geminal R⁸ to form amethylene or a substituted methylene.
 12. The compound of claim 1,wherein at least one of R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) andR^(8f) is taken together with a vicinal R⁸ to form a bond.
 13. Thecompound of claim 1, wherein q is 0 and m is 0 or
 1. 14. The compound ofclaim 1, wherein: R¹ is a substituted or unsubstituted C₁-C₈ alkyl,acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclylor substituted or unsubstituted aryl; each R^(2a) and R^(2b) isindependently H, methyl, fluoro or R^(2a) and R^(2b) are taken togetherto form a carbonyl moiety; each R^(3a) and R^(3b) is independently H orfluoro; each R^(10a) and R^(10b) is independently H, fluoro or methyl orR^(10a) and R^(10b) are taken together to form a carbonyl; and eachR^(11a) and R^(11b) is independently H, fluoro or methyl or R^(10a) andR^(10b) are taken together to form a carbonyl.
 15. The compound of claim1, wherein Q is a substituted or unsubstituted aryl or a substituted orunsubstituted heteroaryl.
 16. The compound of claim 1, wherein Q is asubstituted or unsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl,imidazolyl, furanyl, pyrrolyl or thiophenyl group.
 17. The compound ofclaim 1, wherein Q is substituted or unsubstituted amino, alkoxy,aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino.18. The compound of claim 1, wherein: R¹ is a substituted orunsubstituted C₁-C₈ alkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl; eachR^(2a) and R^(2b) is independently H, unsubstituted C₁-C₈ alkyl or halo;each R^(3a) and R^(3b) is independently H or halo; each X⁷, X⁸, X⁹ andX¹⁰ is CR⁴; each R^(10a), R^(10b), R^(11a) and R^(11b) is independentlyH or methyl; and Q is a substituted or unsubstituted aryl.
 19. Acompound of formula (C-3a) or (C-3b):

wherein; R¹ is CH₃, —CH₂CH₂F, —CH₂CF₃, or —CH₂CH₂C(CH₃)₂OH; R^(4a) is Hor F; R^(4c) is H, CH₃, CF₃, Cl, F, CF₃, or —NHCH₃; R^(9b) is H or F;and R^(9c) is F, CF₃, OCH₃, —CONH(CH₃), or —CON(CH₃)₂. or a salt orsolvate thereof.
 20. The compound of claim 19, wherein R¹ is CH₃; R^(4a)is H; R^(4c) is CH₃, Cl, F or —NHCH₃; R^(9b) is H or F, and R^(9c) is F,OCH₃, —CONH(CH₃) or —CON(CH₃)₂.
 21. The compound of claim 19, wherein R¹is CH₃; R^(4a) is H; R^(4c) is CH₃, Cl, F or —NHCH₃; R^(9b) is H, andR^(9c) is F or OCH₃.
 22. A compound of formula (C-4a) or (C-4b):

wherein; R¹ is CH₃, —CH₂CH₂F, —CH₂CF₃, or —CH₂CH₂C(CH₃)₂OH; R^(4a) is Hor F; and R^(4c) is H, CH₃, CF₃, Cl, F, or —NHCH₃; or a salt or solvatethereof.
 23. The compound of claim 22, wherein R¹ is CH₃; R^(4a) is H;and R^(4c) is CH₃, Cl, F or —NHCH₃.
 24. The compound of claim 22,wherein R¹ is CH₃; R^(4a) is H; and R^(4c) is CH₃, Cl, F.
 25. A compoundof formula (C-5a) or (C-5b):

wherein; R¹ is CH₃, —CH₂CH₂F, —CH₂CF₃, or —CH₂CH₂C(CH₃)₂OH; R^(4a) is Hor F; R^(4c) is H, CH₃, CF₃, Cl, F, or —NHCH₃; and R^(9c) is H, F, CH₃,CF₃, OCH₃, —CONH(CH₃), or —CON(CH₃)₂. or a salt or solvate thereof. 26.The compound of claim 25, wherein R¹ is CH₃; R^(4a) is H; R^(4c) is CH₃,Cl, F or —NHCH₃; and R^(9c) is H, F, or CH₃.
 27. The compound of claim25, wherein R¹ is CH₃; R^(4a) is H; R^(4c) is CH₃, Cl, F; and R^(9c) isH or CH₃.
 28. A compound of formula (C-6a) or (C-6b):

wherein; R¹ is CH₃, —CH₂CH₂F, —CH₂CF₃, or —CH₂CH₂C(CH₃)₂OH; R^(4a) is Hor F; and R^(4c) is H, CH₃, CF₃, Cl, F, or —NHCH₃; or a salt or solvatethereof.
 29. The compound of claim 28, wherein R¹ is CH₃; R^(4a) is H;and R^(4c) is CH₃, Cl, F or —NHCH₃.
 30. The compound of claim 28,wherein R¹ is CH₃; R^(4a) is H; and R^(4c) is CH₃, Cl, F.
 31. A methodof modulating a histamine receptor in an individual comprisingadministering to an individual in need thereof a compound according toclaim
 1. 32. A pharmaceutical composition comprising a compoundaccording to claim 1 and a pharmaceutically acceptable carrier.
 33. Akit comprising a compound according to claim 1 and instructions for use.34. A method of treating a cognitive disorder or a disordercharacterized by causing at least one symptom associated with impairedcognition comprising administering to an individual in need thereof alow dose of a compound according to claim 1, or a pharmaceuticallyacceptable salt thereof.
 35. The compound of claim 1 wherein thecompound is selected from the group consisting of compound 2, 160, 248,253, 254 and 283, or a salt thereof.